imtoken最新版官网|mmtv
作者： imtoken最新版官网
2024-03-07 19:57:22
MMTV-PyMT小鼠|乳腺肿瘤小鼠-赛业（苏州）生物科技有限公司
MMTV-PyMT小鼠|乳腺肿瘤小鼠-赛业（苏州）生物科技有限公司
×
用户注册
用户名
密码
确认密码
姓名
昵称
联系电话
单位
课题组
客户类型
服务条款
同意并接受赛业网站服务条款
注册
注册
我已有帐号，立即,
登录
Toggle navigation
加入我们
登录
注册
China
United States
Toggle navigation
关于我们
赛业大讲堂
市场活动
细胞技术服务
全基因组敲除细胞库
现货KO细胞马上查询
Smart-CRISPR™细胞基因编辑系统
基因敲除细胞自动方案系统
细胞模型构建
稳转细胞株
点突变细胞株
基因敲除细胞株
基因敲入细胞株
基因敲除载体
病毒包装
基因与细胞治疗CRO
基因治疗CRO
靶点预测与验证平台
AAV病毒载体设计与开发
评价模型构建平台
有效性评价服务
CAR-T免疫细胞治疗CRO
抗体开发
CAR分子设计和慢病毒制备
免疫细胞制备
免疫细胞表型检测
体外药效评估
体内药效评估
热门研究领域
眼科研究平台
神经研究平台
小核酸研究平台
模式动物产品与服务
罕见病数据中心（RDDC）
AlphaKnockout基因编辑专家系统
红鼠-小鼠模型资源库
找小鼠，上红鼠
明星鼠模型
热点基因家族
热门研究领域
GFP转基因鼠
药物筛选评价小鼠模型
工具鼠
免疫缺陷模型
人免疫系统重建模型
HUGO-GT™全基因组人源化模型
靶点人源化模型
眼科模型
神经模型
罕见病模型
新冠模型
自发性肿瘤及其他模型
自身免疫疾病模型
代谢模型
人源肿瘤细胞系异体移植（CDX模型）
同源肿瘤异体移植模型（Syngeneic）
动物模型定制服务
TurboKnockout基因编辑小鼠
CRISPR-Pro基因敲除/敲入小鼠
CRISPR-Pro基因敲除/敲入大鼠
转基因小鼠
转基因大鼠
ES打靶基因敲除/敲入小鼠
TALEN基因敲除/敲入鼠
动物模型下游服务
表型分析
小鼠原代细胞提取服务
实验动物进口服务
大小鼠行为学服务
小鼠代繁殖服务
快速扩繁服务
冷冻保存服务
无菌鼠技术平台
无菌鼠
无菌鼠技术服务
{[ x.name ]}
按关键词, 货号或产品名称搜索
想了解细胞产品及试剂相关内容，请点击这里进入OriCell网站
主页
药物筛选评价小鼠模型
自发性肿瘤及其他模型
MMTV-PyMT
工具鼠
免疫缺陷模型
人免疫系统重建模型
HUGO-GT™全基因组人源化模型
靶点人源化模型
眼科模型
神经模型
罕见病模型
新冠模型
自发性肿瘤及其他模型
自身免疫疾病模型
代谢模型
人源肿瘤细胞系异体移植（CDX模型）
同源肿瘤异体移植模型（Syngeneic）
Nppa-Cre小鼠
Pax6-Cre小鼠
H11-Col2a1-iCre小鼠
Pdgfra-Cre小鼠
Clec4f-iCre小鼠
H11-Alb-iCre小鼠
H11-CAG-MerCreMer小鼠
Cyp19a1-IRES-Cre小鼠
H11-Vav1-iCre小鼠
Lyz2-IRES-iCre小鼠
Sftpc-iCre小鼠
Ctsk-iCre小鼠
RCL-GCaMP6f小鼠
H11-Myh6-iCre小鼠
RC-LR-DTR小鼠
Elf5-Cre小鼠
Cx3cr1-iCre小鼠
Vil1-MerCreMer小鼠
H11-EIIA-iCre小鼠
Cdh16-MerCreMer小鼠
RCL-ChR2_H134R/EYFP小鼠
Sftpc-MerCreMer小鼠
SD-CAG-EGFP大鼠
SD-Rosa26-LSL-tdTomato大鼠
C-NKG
C-NKG B2m KO
C-NKG-H2-Ab1 KO
NOD-Scid
CB17-SCID
Rag1 KO
Rag2 KO
BRG
B6RG
Tcra KO
B6J-Ighm Ighd-DKO
BALB/c-Ighm Ighd-DKO
B6-Ighm KO
BALB/c-Ighm KO
B6-Ighj KO
BALB/c-Ighj KO
B6-IgG1 KO
B6-IgA KO
Il12a KO
Il12rb1 KO
B6-Il2rg KO
Alox5 KO
huPBMC-C-NKG小鼠
huHSC-C-NKG小鼠
B6-hRHO-P23H小鼠
B6-hSMN2(SMA)小鼠
B6-htau小鼠
B6-hTARDBP小鼠
B6-hSNCA小鼠
B6-hIGHMBP2小鼠
B6-hMECP2小鼠
B6-hLMNA小鼠
B6-hATXN3小鼠
B6-hTTR小鼠
B6-hSCN2A小鼠
B6-hCFTR小鼠
hF11小鼠
B6-hCD47小鼠
B6-hPDL1-V小鼠
B6-hCTLA4小鼠
B6-hIGHG1小鼠
B6J-hANGPTL3小鼠
B6-hGLP-1R小鼠
B6-hALB (HSA)小鼠
B6-hCALCRL小鼠
B6-hCALCA小鼠
B6-hFCGR1小鼠
hVEGFA-TG小鼠
B6J-hRHO小鼠
B6-Rpe65 R44X
Pde6b KO小鼠
Prph2 KO小鼠
Tub-KO小鼠
Rpe65 KO小鼠
Nr2e3 KO
DMD-Q995*小鼠
FVB-HTT KI(nQ) 小鼠
全人源化罕见病模型
眼科罕见病模型
神经罕见病模型
肌肉罕见病模型
肝脏罕见病模型
代谢罕见病模型
血液罕见病模型
其他罕见病模型
hACE2-All CDS-B6J
hACE2-All CDS-BALBC
hACE2-EGFP
ROSA26-LSL-hACE2
loxP-hACE2-CDStm
Ace2 KO
K18-hACE2-2A-CreERT2
KS（inducible）
KPC
KP
KC model
Apc-Min
MMTV-PyMT
Alb-Cre+/MYC+
H11-CAG-LSL-hMYC-IRES-EGFP
F8 KO
F9 KO
Trp53 KO
Trem2 KO
Hbb-bs&Hbb-bt DKO
Il10 KO
Tlr2 KO
Tlr3 KO
Tlr4 KO
Nod2 KO
Ifnar1 KO
B6-hIL-17A
B6J-Apoe KO
Ldlr KO (em)
Lep KO
Uox-KO
Uox-KO (Prolonged)
Atp7b KO
Foxj1 KO
Usp26 KO
Fah KO
FVB-Abcb1a&Abcb1b DKO (Mdr1a/b KO)
高脂饮食诱导的肥胖小鼠模型（DIO）
２型糖尿病小鼠模型（T2DM小鼠）
1型糖尿病小鼠模型（T1DM小鼠）
饮食诱导非酒精性脂肪肝小鼠模型
化学物质诱发非酒精性脂肪肝小鼠模型
基因编辑非酒精性脂肪肝小鼠模型
复合模型—非酒精性脂肪肝小鼠模型
复合模型—动脉粥样硬化小鼠模型
基因编辑动脉粥样硬化小鼠模型
急性胰腺炎小鼠模型
慢性胰腺炎小鼠模型
在线支持/投诉建议
提交
提交
MMTV-PyMT
产品编号：C001212
背景：C57BL/6J
繁殖：WT x 杂合
小鼠状态：转基因小鼠是可存活的
简介
该转基因品系由小鼠乳腺肿瘤病毒（MMTV）长末端重复序列驱动多瘤病毒中间T抗原（Polyoma Virus middle T antigen, PyMT）的cDNA序列特异性表达。多瘤病毒中间T抗原的表达导致乳腺上皮广泛转化，并迅速产生多灶性乳腺腺癌。
约50%的转基因雌鼠在13周龄时出现可触及的乳腺肿瘤，至19周龄时，成瘤率增长至80%左右。腺癌好发于雌性，偶尔在雄性中也可观察到，它们分化良好，多灶性，最终累及整个乳腺脂肪垫。中间T抗原在乳腺上皮细胞中充当有效的致癌基因，并且表达它的细胞转移潜能增强，在肺中也可发展为继发性转移性肿瘤。
构建方式：MMTV驱动PyMT的cDNA序列特异性表达。
研究应用：该品系可用于乳腺癌和改变肿瘤微环境相关的研究。
模型验证
图1. 13周龄MMTV-PyMT成瘤小鼠的肿瘤生长曲线
MMTV-PyMT小鼠在13周龄时成瘤率约为50%，至19周龄时成瘤率约为80%。该模型成瘤阶段胸腹部乳房肿大，凸出于体表，且随周龄增大而增多增大，部分瘤体在生长过程中可连成一体。
图2. MMTV-PyMT小鼠模型外观（左：16周龄；右：20周龄）
MMTV-PyMT小鼠在13周龄即可观察到乳腺肿瘤，图片中小鼠可观察到明显的乳腺肿瘤。
图3. 24周龄MMTV-PyMT小鼠模型肺部肿瘤
MMTV-PyMT部分小鼠24周龄出现肺部肿瘤，解剖可观测到肺部出现病变，该品系发生肿瘤转移。
图4. 24周龄MMTV-PyMT小鼠肺部HE染色结果
病理组织学观察结果显示，24周龄的MMTV-PyMT病变小鼠肺部存在癌细胞的转移灶，符合模型特点。
如果您对产品或服务有兴趣，可通过以下方式联系我们
在下方表单填写需求描述给我们
点击页面右侧“在线咨询”工具快速咨询
拨打免费电话:400-680-8038
发送邮件至邮箱:
info@cyagen.com
姓名:*
电话:*
邮箱:*
单位:*
需求描述:*
获知途径:*
-- 请选择一个途径 --
{[item.key]}
验证码 *
提交
提交
赛业（苏州）生物科技有限公司
苏州地址:
江苏省苏州市太仓市沙溪镇振溪路69号
美国地址:
2255 Martin Avenue,Suite E, Santa Clara, CA 95050, USA
电话:
400-680-8038
电子邮箱:
info@cyagen.com
网址:
www.cyagen.com
模式动物产品与服务
小鼠资源库
CRISPR-Pro基因敲除/敲入小鼠
TurboKnockout基因编辑小鼠
CRISPR-Pro基因敲除/敲入大鼠
转基因小鼠
转基因大鼠
ES打靶基因敲除/敲入小鼠
敲除载体与细胞构建
Smart-CRISPR™细胞基因编辑系统
基因敲除载体
病毒包装
基因敲除细胞株
过表达细胞株
点突变细胞株
基因敲入细胞株
基因治疗CRO
病毒载体设计与开发
动物模型构建服务
基因治疗有效性评价服务
细胞治疗CRO
慢病毒病毒载体制备
肿瘤免疫模型构建
细胞治疗体内体外药效评价
添加赛业云课堂小助理 进入交流群/领取课件
关注赛业生物订阅号 了解最新资讯
版权所有：赛业生物科技有限公司 Copyright © 2024 Cyagen Biosciences. All rights reserved. 备案号： 苏ICP备16016913号
招聘信息
友情链接
站点地图
交流社区
神经
扫码加入
神经领域交流群
需备注来意,审核后进入
基因
扫码加入
基因领域交流群
需备注来意,审核后进入
细胞
扫码加入
细胞领域交流群
需备注来意,审核后进入
云课堂
扫码加入
云课堂交流群
需备注来意,审核后进入
MMTV-pymt - 知乎
MMTV-pymt - 知乎切换模式写文章登录/注册MMTV-pymt科研辅助同学品系背景：C57BL/6J品系描述：小鼠乳腺肿瘤病毒（Mouse mammary tumor virus: MMTV）是导致小鼠乳腺肿瘤的重要病毒，利用其病毒组织特异启动子及增强子功能，可介导癌基因ERBB2、PyMT、wnt-1在小鼠乳腺高表达而发生乳腺癌。MMTV-PyMT雌鼠、雄鼠均会出现乳腺肿瘤（发病时间待观察），雄鼠乳腺肿瘤发病时间较晚。因此，MMTV-PyMT转基因小鼠模型，可以用于研究乳腺肿瘤的发生、发展及转移，也可用于乳腺肿瘤相关药物的筛选。应用领域：肿瘤研究（乳腺肿瘤）；小分子抗乳腺癌肿瘤药物筛选。发布于 2023-01-31 09:16・IP 属地江苏动物实验动物实验外包实验动物赞同 1添加评论分享喜欢收藏申请
乳腺癌动物模型，你用对了吗？_公司新闻_丁香通
乳腺癌动物模型，你用对了吗？_公司新闻_丁香通
丁香通
丁香园
论坛
丁香客
医药招聘
丁香医生
更多
会议
调查派
用药助手
丁当铺
丁香搜索
医药数据库
来问医生
我要登录
|
免费注册
|
我的丁香通
卖家：
成为卖家
更多合作
买家：
买家中心
移动端
江苏集萃药康生物科技股份有限公司 品牌商
5 年
手机商铺
商家活跃：
产品热度：
搜本店 搜全站
全部产品
查看全部分类
小鼠模型资源
小鼠模型与细胞系定制
科研项目服务
定制繁育服务
商铺首页
公司信息
公司新闻
技术资料
商铺视频
品牌商
江苏集萃药康生物科技股份有限公司
入驻年限：5 年
联系人： 集萃药康
所在地区： 江苏 南京市 浦口区
业务范围： 抗体、细胞库 / 细胞培养、技术服务、试剂、耗材、实验室仪器 / 设备
经营模式： 生产厂商 代理商 科研机构
在线沟通
电话
推荐产品
huHSC-NCG 免疫缺陷小鼠模型 免疫重建模型
询价 询价
BKS-DB 糖尿病小鼠模型
￥475 咨询
NOD-Scid 免疫缺陷小鼠模型 ko模型
询价 询价
H11-K18-ACE2 新冠小鼠模型 人源化小鼠 强启动、KI
询价 询价
APOE 代谢模型 代谢小鼠模型 基因敲除模型
询价 询价
查看全部产品
公司新闻/正文
乳腺癌动物模型，你用对了吗？
人阅读 发布时间：2022-10-20 15:55
根据《2020世界癌症报告》数据显示，2020年全球新发癌症病例1929万例，仅中国新发癌症就有457万人，占全球23.7%，中国癌症新发人数远超世界其他国家，肿瘤疾病人群基数较大。在我国癌症病种中，癌症病种最高的前3位分别是：肺癌、乳腺癌、胃癌。其中，乳腺癌是全球女性高发且导致女性死亡的常见恶性肿瘤，30%～40%早期患者可发展为晚期，而晚期的5年生存率仅20%。
为提高全球范围内女性对乳腺健康的关注，每年的10月18日为世界乳腺癌宣传日，旨在宣传乳腺癌相关知识，提高公众对乳腺癌的关注。
图1：2020年全球范围乳腺癌年龄标准化发病率预估
动物模型是疾病研究及治疗方法探索中必不可少的工具，一个理想的乳腺癌动物模型应与人乳腺癌的肿瘤分子特性及生物行为学等方面存在共性，以便于发病机制的研究及治疗新药的开发。但从癌症的分型来看，单一的动物模型对乳腺癌表型模拟程度有限，因此在实际研究中还需结合具体需求选择合适的动物模型，才能更好地达到研究目的。接下来小编将带大家一起了解一下不同的乳腺癌模型特点及如何选择合适的模型。乳腺癌动物模型
主流的乳腺癌小鼠模型主要分为三类：化学诱导模型、移植瘤模型和基因修饰自发肿瘤模型。01 化学诱导模型
是指通过注射致癌物质如二甲基-苯蒽等诱发小鼠乳腺癌。诱导模型构建简单，诱变剂选择范围大且稳定，诱发成癌率较高，类似于人体肿瘤细胞动力学特征，可用于乳腺癌预防及早期致癌因素的研究。但诱发模型肿瘤发生位点不可预知，同一动物可能有多个肿瘤出现，且肿瘤细胞形态学差异大，不适用于抗癌药物的研究。
02 移植瘤模型
将乳腺癌组织和细胞直接接种于实验动物而建立的模型，在基础研究中应用广泛。根据移植物来源可分为同种移植和异种移植，同种移植动物模型肿瘤生长及转移速度较快，可用来评价乳腺癌发生发展及转移过程中免疫应答的作用。异种移植一般采用人源组织或细胞接种于免疫缺陷小鼠（如重度免疫缺陷鼠NCG），能模拟人恶性肿瘤成瘤后过程，可用于基础和临床研究。但人乳腺癌存在不同的分子分型，且人乳腺癌细胞系相对于其他癌种成瘤难度更大，且不稳定，因此选择合适的细胞系也十分重要。针对乳腺癌不同的分子分型，集萃药康细胞资源库配备丰富的乳腺癌细胞株以及热门靶点人源化改造的细胞资源，用于构建乳腺癌移植瘤模型。
表1：部分集萃药康乳腺癌细胞资源展示[1]ER：雌激素受体；PR：孕激素受体；HER-2：人表皮生长因子受体-2。Luminal A:管腔A型；Luminal B：管腔A型；TNBC：三阴性乳腺癌。
乳腺癌肿瘤细胞系移植模型虽然在基础研究中应用广泛，但在进行临床试验时，细胞系在多代传代过程中已产生遗传变异和肿瘤异质性，不能准确测试药物作用，因此需要构建自发乳腺癌模型来解决这一问题。
03 基因编辑自发肿瘤模型
是指将一个外源基因插入动物的DNA中，使其含有该基因的编码蛋白质高表达或低表达，诱发乳腺癌发生。乳腺肿瘤病毒(mouse mammary tumor virus，MMTV)驱动的致癌基因可导致各种乳腺癌的发生。如MMTV-PyMT小鼠就是通过MMTV驱动多瘤病毒中间T抗原（PyMT）癌基因在乳腺中高表达，诱发乳腺上皮细胞中PyMT基因的表达失控，进而诱发细胞的恶性增殖，导致乳腺癌发生。这种基因编辑自发性乳腺癌模型肿瘤发生时间早，生长速度快，并保留了正常乳腺组织中的各类细胞和精细结构，还原癌细胞发生和生长的微环境，是常用的乳腺癌研究模型[2]。
MMTV-PyMT模型-研究乳腺癌发生发展机制的理想模型
集萃药康通过转基因技术构建了MMTV-PyMT小鼠模型，经验证，小鼠出现乳腺肿瘤的表型，并出现肺及唾液腺转移，可用于研究乳腺肿瘤的发生、发展及转移机制和乳腺肿瘤相关药物的筛选。
图2：MMTV-PyMT 小鼠乳腺、肺及卵巢组织病理学检测
从病理检测结果可见：MMTV-PyMT小鼠存在明显的炎性细胞浸润，并形成乳腺癌巢、乳腺癌转移灶、乳腺导管及曲精小管坏死等现象。
集萃药康除乳腺癌外还可提供肠癌、肝癌、肺癌、胰腺癌等多种癌种自发肿瘤模型，并可根据服务需求提供肿瘤模型定制服务及基于自发肿瘤分离细胞系建系及构建皮下、原位或转移瘤模型，并开展相应的体内药效服务。
表2：集萃药康自发肿瘤模型列表
参考资料
[1]KazuhitoSakamoto , JeffreyW Schmidt,et al.Mouse models of breast cancer[J].MethodsMolBiol. 2015;1267:47-71.
[2]姚祥龙,杨帅等.MMTV-PyMT乳腺癌小鼠模型肿瘤发生的特点[J].安徽师范大学学报,2020,43(4):348-355
[3]李日飞,袁娜等.乳腺癌实验动物模型研究进展[J].中国比较医学杂志,2018,28(2):113-118.
[4]佘锦雯,亓翠玲等.乳腺癌MMTV-PyMT转基因小鼠模型的生物学特性及病理学研究[J].广东药学院院报,2011,27(2):178-182.
上一篇 自发「骨质疏松」模型，了解一下 下一篇 集萃成章丨暨南大学药学院张冬梅教授团队揭示靶向FAPα表达的肝星状细胞治疗对贝伐单抗耐药的CRCLM异种移植血管选定的机制
更多资讯
在线沟通
我的询价
询价列表
点击加载更多
暂时没有已询价产品
发送产品
快捷询价 发送名片
让更多商家联系我
当你希望让更多商家联系你时，可以勾选后发送询价，平台会将你的询价消息推荐给更多商家。
发送
疾病小鼠模型系列之乳腺癌篇 - 知乎
疾病小鼠模型系列之乳腺癌篇 - 知乎首发于小鼠大明星切换模式写文章登录/注册疾病小鼠模型系列之乳腺癌篇南模生物专注模式生物，成就科学价值根据《临床医师癌症杂志》在线发表的“2018年全球癌症统计数据”，去年全球有约210万乳腺癌新发病例，发病率（11.6%）与肺癌并列第一，死亡率（6.6%）位列第五（表1）。在所有患癌女性当中，乳腺癌的发病比例（46.3%）及死亡比例（13.0%）都高居第一[1]，其严重危害着女性的身心健康。乳腺癌小鼠模型能够模拟人体乳腺癌的发生发展，在疾病发生机理研究，药物新靶点发现及临床前药效学评价等方面具有十分重要的理论价值和临床意义。本期小编将带大家了解一下这些常用的乳腺癌模型。表 1 2018年全球主要癌症发病率及死亡率统计乳腺癌模型主要分为移植瘤模型和原发瘤模型两种。乳腺癌移植瘤模型乳腺癌移植瘤模型就是将人体或小鼠原发的乳腺癌组织或细胞移植到小鼠身上使其生长成肿瘤的动物模型。该模型的优点是周期短、成本低，目前在实验室中应用较为广泛。根据移植物来源可分为同种移植和异种移植，其中异种移植采用人源组织或细胞，更接近人体肿瘤真实情况，因此更为普遍，但需要免疫缺陷小鼠作为宿主。由于人类乳腺癌细胞系相对其他癌种成瘤更难，且不稳定，因此对免疫缺陷小鼠的品质更为依赖，采用免疫缺陷程度最高的作为宿主则会大幅度提高乳腺癌细胞系的成瘤率。除去宿主，接种细胞系的选择也尤为重要，选择之前，我们需要先搞清楚将要研究的是哪一类乳腺癌。临床上，乳腺癌根据分子分型[ER（雌激素受体）、PR（孕激素受体）和HER-2（人表皮生长因子受体-2）]分为四类，可分别采用不同的细胞系进行研究（表2）[2][3]。表 2 乳腺癌分子分型及适用细胞系尽管乳腺癌细胞系移植模型在基础研究中应用广泛，但是细胞系难以体现肿瘤异质性的先天不足，限制了其在转化医学研究中的应用。为了测试临床前药物药效，PDX等更为复杂的原发乳腺癌模型应运而生。该模型是将手术中获得的新鲜乳腺癌肿瘤组织移植到免疫缺陷小鼠，常用于药物开发和靶向制剂的个体化用药。由于采用免疫缺陷小鼠（如M-NSG小鼠）作为宿主，还可以在其体内进行人类免疫系统重建（植入人源PBMC或CD34+造血干细胞）以用于肿瘤免疫治疗评估。图 1 乳腺癌PDX模型构建流程示意图乳腺癌原发瘤模型在药物筛选、药效评价或临床预测方面，移植瘤显然有独特的优势。但其缺点也较为明显，例如没有人类乳腺癌组织中的间质细胞，缺少癌细胞周围的三维结构，不能真实模拟人类发病情况，因此，若我们想探究乳腺癌发生或转移的内在机理，显然原发瘤模型更为适合。目前主流的原发瘤模型分为自发型乳腺癌模型、诱导型乳腺癌模型和基因工程小鼠乳腺癌模型。>>>>诱导型乳腺癌模型诱发性乳腺癌模型多采用化学诱发途径，常用的诱导剂有甲基亚硝基脲(N-methyl-N-nitrosourea,MNU)或DMBA等，一般通过灌胃、局部涂抹或静脉注射等途径应用于实验动物，且多采用大鼠进行实验。该方法模型构建周期较长，肿瘤细胞差异性大，恶性行为有限，肿瘤侵袭转移能力较弱，不利于研究恶性乳腺癌发病机理。>>>>基因工程小鼠乳腺癌模型 近些年由于基因编辑门槛降低，基因工程小鼠乳腺癌模型流行起来。通过表达与人类同源的癌基因或敲除抑癌基因，很容易构建与人类发病相似的乳腺癌模型，该模型目前正成为人类研究乳腺癌的核心模型。基因工程小鼠乳腺癌模型大体分类两类，转基因模型和基因敲除模型。转基因乳腺癌模型最常用的方式是在小鼠体内采用乳腺特异性启动子定向表达癌基因。其中乳腺特异性启动子多采用MMTV-LTR，MMTV是导致小鼠乳腺肿瘤的重要病毒，研究人员将其病毒组织特异启动子及增强子功能剥离出来以介导ERBB2（HER-2）、PyMT、Wnt-1等癌基因在乳腺中高表达，进而诱发乳腺癌。目前这几类转基因诱发模型的发病表现及分子机理也相对清晰。例如目前研究较多的MMTV-Wnt-1小鼠，其最早第7周开始出现乳腺瘤，其细胞内Wnt-1基因的高表达可激活自身及邻近细胞膜上的WNT蛋白受体，进而引起乳腺上皮细胞的恶性转化[4]。MMTV-PyMT小鼠，第8周开始发病，第14周达到晚期乳腺癌水平，其乳腺癌相关转录因子Runx1随着病程发展进而表达上升[5]。MMTV-ERBB2雌鼠生长到6-12月龄自发长出乳腺肿块，因为ERBB2的表达往往与患者的预后负相关，因此该模型相对使用较少，但在ERBB2阳性乳腺癌研究中有重要作用。基因敲除乳腺癌模型在小鼠体内敲除抑癌基因也可以建立乳腺癌模型，例如最为经典的抑癌基因p53。但因为全身敲除p53除了诱发乳腺癌还会引起淋巴瘤等其他肿瘤（在C57BL/6或129/Sv背景下，p53缺失优先诱发肉瘤和淋巴瘤，与BALB/c回交多代后才可以大幅度提高乳腺癌发生几率），且很多抑癌基因如PTEN，BRCA（Breast tumor suppressor gene）等敲除可导致胚胎致死，因此乳腺组织特异性基因敲除应运而生。该模型采用Cre-loxp系统，需要使用两种小鼠，第一种为乳腺特异性表达的Cre小鼠，例如WAP-Cre和MMTV-Cre小鼠；第二种为抑癌基因的flox小鼠，例如BRCA1（fl/fl）小鼠，E-cadherin（fl/fl）小鼠等，两种小鼠交配就可以定向在乳腺组织中敲除抑癌基因以诱发乳腺癌。在研究过程中，也经常采用抑癌基因条件性敲除和全身性敲除联合使用的情况，比如BRCA1的乳腺组织敲除联合p53基因的全身杂合突变，即BRCA1（fl/fl），MMTV-Cre+，p53（+/-）小鼠等。在实际研究过程中除了要考虑小鼠品系、发病周期、发病率等因素外，当然还要了解各基因工程小鼠模型所诱发乳腺癌的分子分型（表 3）[6]以最大程度契合自己的研究需求。表 3 乳腺癌分子分型及其适用的部分基因工程小鼠乳腺癌类型基因工程小鼠基因型发病情况基因工程小鼠乳腺癌模型在研究肿瘤发生的分子机制、病理机制及抗癌药物筛选中有着至关重要的作用，其形成肿瘤的形态特征与人类肿瘤的自然发生极为相似，目前正成为乳腺癌领域必不可少的研究工具。南模生物有包括乳腺癌在内多个癌种的小鼠肿瘤模型，并且可根据客户的研发需要提供诱发性肿瘤小鼠模型、基因工程小鼠肿瘤模型定制、PDX模型以及各类基于细胞系的异体移植肿瘤模型服务。我们可以构建各类皮下，原位或者转移瘤模型，并针对相应的模型提供高度定制化的体内药效学服务。更多资讯，请关注南模生物公众号。http://weixin.qq.com/r/sS0HH0rEJRdarQ5893ij (二维码自动识别)参考^ Freddie B , Jacques F , Isabelle S , et al. Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA: A Cancer Journal for Clinicians, 2018.^Holliday D L , Speirs V . Choosing the right cell line for breast cancer research[J]. Breast Cancer Research Bcr, 2011, 13(4):215.^Whittle J R , Lewis M T , Lindeman G J , et al. Patient-derived xenograft models of breast cancer and their predictive power[J]. Breast Cancer Research, 2015, 17(1):17.^Parkin N T , Kitajewski J , Varmus H E . Activity of Wnt-1 as a transmembrane protein.[J]. Genes & Development, 1993, 7(11):2181-2193.^Browne G , Taipaleenm?Ki H , Bishop N M , et al. Runx1 is associated with breast cancer progression in MMTV-PyMT transgenic mice and its depletion in vitro inhibits migration and invasion[J]. Journal of Cellular Physiology, 2015, 230(10):2522-2532.^Sakamoto K , Schmidt J W , Wagner K U . Mouse Models of Breast Cancer[J]. Methods Mol Biol, 2015, 1267:47-71.编辑于 2020-04-01 16:53肿瘤实验动物基因编辑赞同 422 条评论分享喜欢收藏申请转载文章被以下专栏收录小鼠大明星基因修饰小鼠模
乳腺癌动物模型，你用对了吗？-丁香实验
物模型，你用对了吗？-丁香实验48小时，有问必答丁香实验，轻松科研已收录 10000+ 实验48小时，有问必答丁香实验，轻松科研已收录 10000+ 实验48小时，有问必答登录提问提问我要登录｜免费注册丁香通首页|乳腺癌动物模型，你用对了吗？点赞收藏分享乳腺癌动物模型，你用对了吗？集萃药康2023-01-303225根据《2020 世界癌症报告》数据显示，2020 年全球新发癌症病例 1929 万例，仅中国新发癌症就有 457 万人，占全球 23.7%，中国癌症新发人数远超世界其他国家，肿瘤疾病人群基数较大。在我国癌症病种中，癌症病种最高的前 3 位分别是：肺癌、乳腺癌、胃癌。其中，乳腺癌是全球女性高发且导致女性死亡的常见恶性肿瘤，30%～40% 早期患者可发展为晚期，而晚期的 5 年生存率仅 20%。为提高全球范围内女性对乳腺健康的关注，每年的 10 月 18 日为世界乳腺癌宣传日，旨在宣传乳腺癌相关知识，提高公众对乳腺癌的关注。
图 1. 2020 年全球范围乳腺癌年龄标准化发病率预估
动物模型是疾病研究及治疗方法探索中必不可少的工具，一个理想的乳腺癌动物模型应与人乳腺癌的肿瘤分子特性及生物行为学等方面存在共性，以便于发病机制的研究及治疗新药的开发。但从癌症的分型来看，单一的动物模型对乳腺癌表型模拟程度有限，因此在实际研究中还需结合具体需求选择合适的动物模型，才能更好地达到研究目的。接下来小编将带大家一起了解一下不同的乳腺癌模型特点及如何选择合适的模型。
乳腺癌动物模型主流的乳腺癌小鼠模型主要分为三类：化学诱导模型、移植瘤模型和基因修饰自发肿瘤模型。
一、化学诱导模型
是指通过注射致癌物质如二甲基苯蒽等诱发小鼠乳腺癌。诱导模型构建简单，诱变剂选择范围大且稳定，诱发成癌率较高，类似于人体肿瘤细胞动力学特征，可用于乳腺癌预防及早期致癌因素的研究。但诱发模型肿瘤发生位点不可预知，同一动物可能有多个肿瘤出现，且肿瘤细胞形态学差异大，不适用于抗癌药物的研究。
二、移植瘤模型
将乳腺癌组织和细胞直接接种于实验动物而建立的模型，在基础研究中应用广泛。根据移植物来源可分为同种移植和异种移植，同种移植动物模型肿瘤生长及转移速度较快，可用来评价乳腺癌发生发展及转移过程中免疫应答的作用。异种移植一般采用人源组织或细胞接种于免疫缺陷小鼠（如重度免疫缺陷鼠 NCG），能模拟人恶性肿瘤成瘤后过程，可用于基础和临床研究。但人乳腺癌存在不同的分子分型，且人乳腺癌细胞系相对于其他癌种成瘤难度更大，且不稳定，因此选择合适的细胞系也十分重要。针对乳腺癌不同的分子分型，集萃药康细胞资源库配备丰富的乳腺癌细胞株以及热门靶点人源化改造的细胞资源，用于构建乳腺癌移植瘤模型。
表 1. 部分集萃药康乳腺癌细胞资源展示[1]
ER：雌激素受体；PR：孕激素受体；HER-2：人表皮生长因子受体-2。Luminal A：管腔 A 型；Luminal B：管腔 A 型；TNBC：三阴性乳腺癌。
乳腺癌肿瘤细胞系移植模型虽然在基础研究中应用广泛，但在进行临床试验时，细胞系在多代传代过程中已产生遗传变异和肿瘤异质性，不能准确测试药物作用，因此需要构建自发乳腺癌模型来解决这一问题。
三、基因编辑自发肿瘤模型
是指将一个外源基因插入动物的 DNA 中，使其含有该基因的编码蛋白质高表达或低表达，诱发乳腺癌发生。乳腺肿瘤病毒(mouse mammary tumor virus，MMTV)驱动的致癌基因可导致各种乳腺癌的发生。如 MMTV-PyMT 小鼠就是通过 MMTV 驱动多瘤病毒中间T抗原（PyMT）癌基因在乳腺中高表达，诱发乳腺上皮细胞中 PyMT 基因的表达失控，进而诱发细胞的恶性增殖，导致乳腺癌发生。这种基因编辑自发性乳腺癌模型肿瘤发生时间早，生长速度快，并保留了正常乳腺组织中的各类细胞和精细结构，还原癌细胞发生和生长的微环境，是常用的乳腺癌研究模型[2]。
MMTV-PyMT 模型-研究乳腺癌发生发展机制的理想模型
集萃药康通过转基因技术构建了 MMTV-PyMT 小鼠模型，经验证，小鼠出现乳腺肿瘤的表型，并出现肺及唾液腺转移，可用于研究乳腺肿瘤的发生、发展及转移机制和乳腺肿瘤相关药物的筛选。
图 2. MMTV-PyMT 小鼠乳腺、肺及卵巢组织病理学检测
从病理检测结果可见：MMTV-PyMT 小鼠存在明显的炎性细胞浸润，并形成乳腺癌巢、乳腺癌转移灶、乳腺导管及曲精小管坏死等现象。
集萃药康除乳腺癌外还可提供肠癌、肝癌、肺癌、胰腺癌等多种癌种自发肿瘤模型，并可根据服务需求提供肿瘤模型定制服务及基于自发肿瘤分离细胞系建系及构建皮下、原位或转移瘤模型，并开展相应的体内药效服务。
表 2. 集萃药康自发肿瘤模型列表
参考文献
[1] KazuhitoSakamoto , JeffreyW Schmidt,et al.Mouse models of breast cancer[J].MethodsMolBiol. 2015;1267:47-71.
[2] 姚祥龙,杨帅等.MMTV-PyMT 乳腺癌小鼠模型肿瘤发生的特点[J].安徽师范大学学报,2020,43(4):348-355
[3] 李日飞,袁娜等.乳腺癌实验动物模型研究进展[J].中国比较医学杂志,2018,28(2):113-118.
[4] 佘锦雯,亓翠玲等.乳腺癌 MMTV-PyMT 转基因小鼠模型的生物学特性及病理学研究[J].广东药学院院报,2011,27(2):178-182.预览相关问答问乳腺癌干细胞和乳腺癌干性是一回事儿吗3 回答 267 围观2023-04-29问乳腺癌造模3 回答 309 围观2022-09-30问动物模型2 回答 225 围观2022-09-13相关方法FISH 检测乳腺癌中 HER2 扩增实验2022-02-11肺热证动物模型2022-02-11脾不统血证动物模型2022-02-11推荐阅读乳腺癌DNA聚合酶，你选对了吗？相对定量，你的内参选对了吗？提问48 小时有问必答扫一扫实验小助手关注公众号反馈TOP打开
干货：九大肿瘤相关信号通路介绍-Wnt基因家族与肿瘤分子靶向治疗（三） - 知乎
干货：九大肿瘤相关信号通路介绍-Wnt基因家族与肿瘤分子靶向治疗（三） - 知乎切换模式写文章登录/注册干货：九大肿瘤相关信号通路介绍-Wnt基因家族与肿瘤分子靶向治疗（三）晶锐生物专注于解决基因编辑疑难杂症！一：前言1982年在小鼠乳腺癌发现了Wnt基因，由于此基因激活依赖小鼠乳腺癌相关病毒基因的插入，因此，当时被命名为Int1基因，之后的研究表明，Int1基因在小鼠正常胚胎发育中起重要作用，相当于果蝇的无翅（Wingless)基因，可控制胚胎的轴向发育。此后大量研究提示了Int1基因在神经系统胚胎发育中的重要性，因此将Wingless与Int1结合，称为Wnt基因。人Wnt基因定位于12q13.在胚胎发育中，Wnt基因调控的重要信号传导系统即为Wnt通路。二：WNT基因家族以及通路Wnt 基因家族(Wingless-type MMTV integration site family，无翅型MMTV病毒整合位点家族)是一组在多细胞动物中都有表达的高度保守的原癌基因，从低等生物到高等动物，Wnt 基因家族成员都有高度的同源性。Wnt 通路主要有3条途径:1. 经典Wnt信号途径，即Wntβ2连环蛋白信号途径，通过β2连环蛋白在核中积累，启动Wnt 相关靶基因，调控细胞的增殖和分化。2. 平面细胞的极性(the planar cell polarity，PCP)途径，主要作用是在胚胎发育阶段调控细胞骨架的重排。3.WntP Ca2+ 途径，该通路有Wnt25α或Wnt211激活，通过钙调蛋白依赖的激酶、钙调磷酸酶其作用，激活卷曲蛋白受体后释放 Ca2+ 并激活蛋白激酶C, 诱导细胞内 Ca2+ 浓度增加，活化T细胞核因子，可能通过调节细胞粘附，发挥抑癌作用。三：WNT通路研究现状当存在Wnt信号时，Wnt信号与细胞膜卷曲蛋白-低密度脂蛋白受体相关蛋白(Fzd-LRP)复合物结合，Axin移至细胞膜，转录激活因子β-连环素(β-catenin)入核作用于Tcf/lef并召集转录激活因子，促进 Wnt 靶基因的转录。当缺乏 Wnt信号时，β-catenin 在蛋白复合物作用下主动降解而维持在较低水平，该复合物包括结直肠瘤性息肉病蛋白(APC蛋白)、糖原合成酶3β(GSK3β)及蛋白激酶CK1a。T细胞特异性转录因子/淋巴增强因子(Tcf/lef)复合物作用于转录抑制因子，并阻断靶基因的表达。约90%散发性结肠癌患者可发生 Wnt 通路异常，主要由 APC 突变所致，其次是β-catenin 或Axin2 突变。β-catenin 突变导致的 Wnt 通路异常也可见于肝癌、卵巢癌、皮肤癌、前列腺癌、黑色素瘤及 Wilms 瘤。Wnt基因并不直接通过自身基因的突变诱发恶性肿瘤，而是通过信号传导过程引发一系列不同的基因缺陷，从而诱发癌症或肿瘤增殖，或通过表达水平的提高调控靶基因，促进组织细胞增殖，从而诱发恶性肿瘤。到目前为止，经过许多分子生物学实验，最肯定的机制就是，Wnt信号通过沉降β-catenin，造成的异常基因激活。Wnt-1、Wnt-2、Wnt-3和Wnt-4的过表达可以造成乳腺上皮的形态学转变。Wnt-5在皮肤恶性黑色素瘤中过表达，已经作为肿瘤标记物被确定。Wnt-11可通过促进肿瘤向神经内分泌分化，促进肿瘤细胞存活，增强细胞侵袭转移能力诱发卵巢癌。四：关键因子简述1:Wnt 受体Wnt受体卷曲蛋白是一组7次穿膜的跨膜蛋白，在哺乳类发现已有10种，其按极端配体结合区富含半胱氨酸，可与 Wnt 信号因子结合激活信号传导。2:Dsh 蛋白Dsh 蛋白是Wnt 通路正性调节者，位于卷曲蛋白下游、β连环蛋白上游，包括 Dsh蛋白1、Dsh蛋白2、Dsh蛋白3。研究发现，与自体正常肺组织相比。Dsh蛋白3在75%非小细胞肺癌组织中过度表达，且靶向抑制Dsh蛋白1、Dsh蛋白2和Dsh蛋减少环蛋白表达、阻断T细胞因子依赖的转录和抑制人非小细胞肺癌生长。3:β连环蛋白国内学者报道，β连环蛋白在正常支气管上皮细胞和腺细胞膜表达，且染色强度均一，尽管在腺癌、鳞癌中β连环蛋白主要表达在膜上,但染色强度降低,呈不均一性，38.3%肿瘤组织中存在膜表达下降或缺失。细胞膜上β连环蛋白的表达下降必然降低细胞间隙粘附能力，为细胞发生侵袭、转移提供了前提条件。此外，肿瘤细胞内胞质β连环蛋白积蓄，51.7%细胞核染色阳性，游离β连环蛋白水平上升，可能驱动β连环蛋白入核。4:APC基因APC基因已经被证实为一种肿瘤抑制基因，多种肿瘤中发现其DNA高度甲基化而失活。据研究表明，在非小细胞癌的中，95%肿瘤组织存在 APC 基因内高度甲基化。同时，肺癌患者的支气管抽吸液中也可检测到APC的DNA甲基化，非小细胞肺癌为71%，小细胞肺癌为38%，推测APC基因的DNA甲基化可能是其在肺癌中表达降低的原因之一。五：学习交流群最后对肿瘤信号通路+单细胞测序培训+国自然课题研究方案感兴趣的朋友可以添加小助手微信jingruishengwu，进入肿瘤信号通路交流群以及相关学习讨论群。相关培训视频可以关注晶锐生物测序视频号观看。发布于 2023-05-27 12:02・IP 属地广东癌症靶向治疗肿瘤赞同 1添加评论分享喜欢收藏申请
CCTV.com-科学家称小鼠乳腺肿瘤病毒（MMTV）导致乳腺癌
CCTV.com-科学家称小鼠乳腺肿瘤病毒（MMTV）导致乳腺癌
新闻 | 体育 | 娱乐 | 经济 | 科教 | 少儿 | 法治 | 电视指南 | 社区 论坛 博客 播客 | 网络电视直播 点播 | 手机MP4
首页 >人文探索子网 >快报快评 > 正文
打印本页
转发
收藏
关闭
定义你的浏览字号:
科学家称小鼠乳腺肿瘤病毒（MMTV）导致乳腺癌
央视国际 www.cctv.com 2007年06月22日 19:40 来源：中国新闻网
一些科学家提出，与人类乳头状瘤病毒引起宫颈癌类似，另一种或几种病毒也同样可能是人类乳腺癌的元凶。病毒导致乳腺癌？
早在1930年，生物学家约翰?比特尼就曾研究过一个家族内有乳腺癌的老鼠品系。
这项研究一开始认为乳腺癌是有遗传原因的，但是后来发现，如果让小老鼠在出生后离开母亲转而由其他母鼠哺育，则这些小老鼠日后就不会发生乳腺癌。
比特尼很快意识到这个问题的答案在有乳腺癌倾向的老鼠乳汁中：一定是乳汁引起的肿瘤。在随后的研究中，人们终于找到了一种致病病毒，叫做小鼠乳腺肿瘤病毒(MMTV)。这一发现让另一个明显的问题凸现出来：人类的部分乳腺癌是不是也可能由一种类似的病毒引起呢？
答案似乎是合理的。但到现在为止，人们还没有发现支持病毒导致乳腺癌的确凿证据。也没有母乳喂养和癌症有关的线索。事实上，当前用母乳喂养孩子的妇女越来越少，乳腺癌的发生比例反而越来越高。到了上世纪70年代，这种病毒致癌的说法渐渐被人淡忘，没有多少人再继续关注这一话题。
然而，几十年后的今天，人们仍然没有找到90%乳腺癌的成因。直到最近，有人重新回想起病毒致癌的说法，认为至少在一些零星的病例中，与MMTV类似的病毒可能是乳腺癌的元凶。假如真是这样，这可是一则好消息。因为，小鼠的乳腺癌可以通过MMTV的疫苗来防治，人同样也能以疫苗来拯救性命。
这个想法的支持者举出了过去10年间的研究成果。研究显示，有一种类似于MMTV的病毒存在于1/3的人乳腺肿瘤中。不过，也有不少相反的研究结果。现在，已经要到解开这个谜题的时候了。
人类乳腺癌缘起老鼠？
虽然上世纪70年代人们对MMTV和人类关系的兴趣逐渐下降，但仍然有人继续研究这一课题。MMTV是一种复杂的利用宿主免疫系统的逆转录酶病毒，它能将其基因插入到宿主的染色体中。它可以在乳腺细胞保持很多年的休眠状态，直到一个母鼠达到性成熟并怀孕后，MMTV才再次活跃起来。
当绝大多数研究人员将注意力集中在找出MMTV怎样让小鼠患癌的时候，一小部分人开始思考MMTV对研究人员会产生什么后果。20世纪80年代，美国新泽西加登癌症中心的阿诺德?戴恩发现一些实验室的工作人员对MMTV表现出一种免疫反应，说明他们已经感染了这种病毒。其中一位女性在查出该病毒感染阳性后不久就得了乳腺癌。
1995年，纽约西奈山医学院的比琪兹?颇戈和同事利用PCR技术做了一项研究。PCR是一种用来检测微量特异DNA序列的一项技术，他们检查了组织样本中叫做env的一个MMTV基因组成序列。结果发现，乳腺癌样本中38%的序列和它配对，但是在正常的乳腺组织中或其他肿瘤中没有这样匹配的DNA片段。
接下去的几年，还有一些研究小组报道类似的研究成果。2000年，纽约医学院的波利?艾特坎不仅在人类的乳腺癌组织中找到了MMTV序列，还发现一些样本中存在着不只一个品系的MMTV，说明目前该病毒感染的复杂性。2003年，时在瑞典隆德大学就职的卡罗琳?福特在42%澳洲妇女的乳腺癌样本中检测到MMTV序列，同时发现，正常的乳腺组织中只有1.8%(111个样本中有2个)的MMTV序列。
福特小组也发现，2/3的男性乳腺癌组织中可检测到MMTV。
感染从何而来
回过头来问，假如MMTV或者另一种类似的病毒真是导致乳腺癌的元凶，那么，人类是如何被感染的？似乎很明显的是，人类乳腺癌并不是通过母乳传染病毒的。1998年，琳达?提图斯-俄恩思道夫在美国达特茅斯医学院进行了一个由大约8000名妇女参与的研究，结果没有发现母乳喂养会增加乳腺癌发生的危险，即便母亲后来发展为乳腺癌，也不会增加被哺育孩子患癌的风险�D�D一种常识是，哺乳会显著降低母亲患乳腺癌的风险。
既然病毒不是从乳汁传递而来，那么，是不是由老鼠直接感染给人的呢？在理论上，MMTV可以借昆虫比如跳蚤或蚊子从小鼠传染给人，或者，直接由老鼠碰过的食物传给人。很多国家的法规中都容忍在谷物中存有一定量的老鼠屎。
为了研究这一关系，1999年，加拿大渥太华大学的托马斯?斯图尔特做了一个有趣的研究，他将人乳腺癌的发病率与老鼠种类的分布做比较。发现在全球范围内，乳腺癌的发病率存在巨大差异：某些西方国家的发病率要比一些远东国家的发病率高出5倍之多。而这种变数不可能是遗传的，因为移民到美国的孩子和当地的每个人一样遭受着同样的乳腺癌高发率。另外，迄今为止，还没有发现乳腺癌和任何单一的环境因子比如饮食存在特别强烈的相关性。
斯图尔特发现，在全球范围内，在那些有一种特别的家鼠亚种分布的地区，乳腺癌的发生率趋于升高。该亚种原是西欧的本地物种，目前业已随着殖民者蔓延到全球的很多地区，包括北美洲、澳大利亚和新西兰，有证据表明，这种家鼠比其他老鼠种类更倾向于发生MMTV感染。
因此，对MMTV序列的研究结果与病毒解释乳腺癌发生率存在地区差异的想法刚好吻合。在西方国家，大约有10%的女性患乳腺癌，同时在美国、澳大利亚和意大利的1/3乳腺肿瘤中发现有MMTV序列。而在越南，只有1%的妇女患乳腺癌。2003年，当福特在研究中查看越南妇女的样本时，她发现，只有0.8%的肿瘤样本中有MMTV序列，而正常乳腺组织样本中没有MMTV序列。
反对的声音
虽然这些研究结果已经勾画出一幅似乎合理的图画，但是，很多研究人员还没有确信这种说法。罗伯特?盖瑞是新奥尔良杜兰大学的病毒学家，他发现与MMTV类似的序列不仅存在于乳腺肿瘤中，也存在于10%健康男女的组织中。这就是说，逆转录病毒已经整合到某些人的染色体中了。
这种说法当然也是合理的：有几个易感乳腺癌的实验室小鼠品系，在它们体内的逆转录病毒已经永久性地整合在染色体上，因而可由父母传递给后代。盖瑞说：“我们不能消除由老鼠传播至人类的可能性，不过，我觉得它更像是一种内源性病毒。”
另外一些研究小组则没有能在乳腺肿瘤的样本中找到MMTV序列。比如，2004年，英国GKT医学院由约翰?卡森领导的一个小组就没有在伦敦病人的乳腺癌样本中发现env基因序列。
另外，诺贝尔奖得主、美国麻省怀特海德生物医学研究所的罗伯特?温伯格指出：没有人仅凭癌细胞上的一个基因片段就把MMTV认为是引起细胞癌变的病毒。他认为：分子技术才诞生几十年，要获得MMTV基因序列以及致癌的确凿证据，还需要时间。
对MMTV理论的另一种批评是：乳腺癌的风险并不会被免疫抑制而提高。卡森说：“如果你查看其他由病毒引起的癌症，比如宫颈癌，它们通常更容易在那些免疫系统功能低下的人群中发病。”卡森认为乳腺癌与免疫低下没有关系是反对该假说的最有力证据。
但是，这一假说的捍卫者指出：MMTV传播利用的就是宿主免疫系统，至少在老鼠身上，它最初的传播是通过MMTV超级抗原引起了免疫细胞的增殖所达成的，因此，若在这个阶段实施免疫抑制就有可能阻止病毒到达乳腺。
假说难以建立
虽然老鼠的乳腺癌病毒MMTV已经获得了很多关注，但它还不是惟一可能引起人乳腺癌的病毒。引起宫颈癌的人类乳头状瘤病毒(HPV)也是乳腺癌的一个疑凶。一些研究已经在乳腺肿瘤的样本中发现HPV感染的证据。如果人类乳头状瘤病毒确实在乳腺癌的发生中有这种作用，那么新的宫颈癌疫苗就应该将乳腺癌的发病率减低。
另外一种有嫌疑的病毒是人类疱疹病毒(EBV)，这种病毒感染90%的人群。目前已被认为是引发鼻咽癌、喉癌和白血病的原因。科学家认为，人们在不同的年龄发生的感染将导致不同的癌。
阻止健康细胞癌变需要一系列的步骤，先要使细胞失去功能，而病毒可以利用多种途径参与这一过程。
有一些病毒携带着一些促进细胞生长失控的特别基因。比如人类乳头状瘤病毒就能让引发细胞自杀的人类蛋白质失活，使得细胞开始失去控制地生长。病毒对健康细胞还有更微妙和间接的影响。比如，由B型肝炎或C型肝炎病毒引起的长期肝炎会导致肿瘤形成。这些远不是病毒对感染细胞所造成的直接影响。
从一个人感染了一种病毒，到最后发展成为癌症可能需要几十年。相同病毒的不同品系在致癌能力上变数很大，有些病毒还能引发不止一种癌。还有一种或两种病毒在发动细胞癌变的过程之后，自己从宿主体内消失。
鉴于这些以及更多的原因，人们很难建立起某种病毒是否引起人类癌症的假说。
无论是颇戈还是福特，都认为他们的研究只是提出了一种可能性，整个的研究工作尚在起步阶段。目前，还没有哪个MMTV假说的支持者站出来说，他们已经获得了结论性的证据。
要说服反对者，最好的办法就是将完全的MMTV病毒颗粒从肿瘤样本中分离出来，但是，这项工作没有那么容易。盖瑞说：“从组织中寻找病毒，过去和现在都一样困难。”
有意思的是，颇戈已经开始向这个高难目标迈步了。她说，借助电子显微镜，她已经在癌细胞中看到了病毒颗粒，还看到了分布在细胞表面的新生病毒颗粒。不过，严格的实验结果还需要等待正规出版物发表才能算数。
责编：常颖
第1/1页
CCTV10精彩视频
更多新闻>>
解密羽毛球
拉勾（上）
“电脑导航”创奇迹
“公主”的成长
[科技博览]“飞檐走壁”为哪桩[家庭]快乐老李[探索发现]秘境追踪精选版之机械人类[人物]一个与现代舞不可分割的名字――曹诚渊[百家讲坛]王立群读《史记》（十八）另类人才[绿色空间]小象诞生系列：小象的磨难 [视频]刘赐被告抢占民田[视频]汉武帝对跳槽案不做处理[子午书简]“我爱诵读”天津站2[子书午简]“我爱诵读”天津站1[百家讲坛]易中天品三国（四十五）情天恨海[天天饮食]绿豆冰沙：清凉爽口，香甜解暑[天天饮食]豆浆凉面：清凉爽口，豆香浓郁[天天饮食]苦瓜炒虾肉：口感鲜嫩，咸香爽口[家庭]盲人穆孟杰的爱情[视频]淮南王刘安意图谋反[子午书简]谁是“诵读高手”（五）[人物]一代球王马拉多纳（下）[家庭]梁用的故事[科技博览]揭密神弩（下）
热点推荐
更多新闻>>
德国开发出全新电路系统 可实现用人体体温发电《西游记》中孙悟空为什么“无性”？ 国产3G下月少量放号 明年初前或发临时牌照中国古代十大著名酒局古代中国为什么只选出四大美女?重庆"鬼屋"一家4口陆续早逝网通宣布10省市固话同城移机不改号花果山出现云窗、云帘景观1949年10月1日，蒋介石听收音机至深夜新型电脑病毒加密用户文件勒索300美元美国加州发现新品种兰花 散发气味恶臭难闻研究称冰河期洪水冲出英吉利海峡 英国变小岛鲨鱼面临威胁美太空厕所造价1900万美元[视频]媒体博览:大象被迫学探雷我国开通海事卫星手机业务 08年全球覆盖东芝全球召回1万块索尼产笔记本电池可视电话标准颁布 3G临近？英特尔发布最快的Core2 Extreme处理器 传统建筑比现代建筑更环保节能？
精彩专辑
更多>>
相关视频
CCTV-1 CCTV-2 CCTV-3 CCTV-4 CCTV-5 CCTV-6 CCTV-7 CCTV-8
CCTV-9 CCTV-10 CCTV-11 CCTV-12 CCTV-新闻 CCTV-少儿 CCTV-音乐 CCTV-E&F
CCTV介绍 |
CCTV.com介绍 |
央视人力资源储备库 |
版权声明 |
联系我们 |
广告服务 |
友情链接
中国中央电视台 版权所有
京ICP备05065290号 网上传播视听节目许可证号 0102004
系统集成：长天集团 网页设计：中视河图
");
//-->
湘雅医院：新突破，RNA测序揭示乳腺癌遗传模型，促进乳腺癌疫苗开发_澎湃号·湃客_澎湃新闻-The Paper
：新突破，RNA测序揭示乳腺癌遗传模型，促进乳腺癌疫苗开发_澎湃号·湃客_澎湃新闻-The Paper下载客户端登录无障碍+1湘雅医院：新突破，RNA测序揭示乳腺癌遗传模型，促进乳腺癌疫苗开发2023-07-20 13:25来源：澎湃新闻·澎湃号·湃客字号原创 转网 转化医学网本文为转化医学网原创，转载请注明出处作者：Floyd导读：乳腺癌占每年新发癌症病例的12%，已成为成人恶性肿瘤中最常见的癌症。HER2靶向治疗已经显著改善了乳腺癌的治疗。MMTV-neu和MMTV-PyMT小鼠已被广泛研究作为乳腺癌研究的模型。近日，湘雅医院团队在《Cell Discovery》上发表题为“New mouse genetic model of breast cancer from IKKα defects in dendritic cells revealed by single-cell RNA sequencing”的文章。文章指出，IκB激酶α (IKKα)是经典IKK复合物的两个催化亚基之一，属于NF-κB信号传导的上游，在包括KRAS突变的肺腺癌的发生在内的癌变过程中起着关键作用。IKK复合物的另一个亚基IKKβ缺乏会导致树突状细胞(DC)迁移和免疫耐受受损。有趣的是，我们发现小鼠DC中IKKα的条件敲除(IKKα△Itgax)意外地诱导自发性肿瘤出现在乳腺附近，在老年小鼠(≥20周龄，23/58)中肿瘤发生率约为39.6%，脾脏重量增加，脾肿大频繁。此外，我们发现IKKα在IKKα△Itgax小鼠的骨髓源性DC中确实被敲除，而IKKα水平在其他几个组织中是正常的。然而，这种自发性肿瘤的病理类型和起源尚不清楚，探索乳腺癌免疫微环境的小鼠模型的可靠性也有待检验。https://www.nature.com/articles/s41421-023-00553-z研究背景01近年来，单细胞RNA测序(scRNA-seq)已被广泛用于恶性细胞和肿瘤类型的来源鉴定。因此，我们应用scRNA-seq系统地鉴定了这种未知的肿瘤类型。我们还从Tabula Muris数据库中下载了11个组织scRNA-seq数据集。然后我们进行了PCA分析，发现正常乳腺组织和肿瘤组织具有相似的基因表达模式和相似的免疫表型，这表明IKKα△Itgax小鼠的肿瘤可能起源于乳腺组织。为了进一步确定IKKα△Itgax小鼠肿瘤的乳腺样特性，我们通过无监督方法检测了12个细胞簇，每个簇都用已知的标记进行注释以对这些细胞进行分类。UMAP图显示上皮细胞中Erbb2和Vimentin富集。为了确定IKKα△Itgax小鼠肿瘤的驱动基因，我们通过比较不同肿瘤细胞群和正常乳腺细胞群来鉴定差异表达基因(DEGs)。我们发现，与正常乳腺细胞相比，肿瘤上皮细胞中S100a8、Erbb2和Tnfrsf1b富集。为了研究基因标记的功能意义，我们在肿瘤细胞和正常乳腺细胞之间进行了单样本基因集富集分析(ssGSEA)。与正常乳腺组织相比，肿瘤上皮细胞中的靶向Kras和糖酵解信号上调，提示IKKα缺陷诱导的自发性肿瘤可能起源于上皮细胞。通过scRNA-seq和免疫组化鉴定小鼠肿瘤病理和起源既往证据表明，通过轨迹分析，上皮细胞具有肿瘤细胞从癌前状态到恶性状态的分化状态和基因表达模式，可用于研究癌变的分子特征。然后我们构建了肿瘤细胞和正常上皮细胞的转录轨迹。肿瘤上皮样本沿正常上皮细胞形成具有5个转录状态(S1 - S5)的分支结构，标志着正常上皮细胞的不同分化状态，而正常上皮细胞大多位于S1 。我们使用大规模拷贝数变异(CNVs)来推断这种肿瘤细胞来源，我们发现肿瘤上皮细胞中存在7q、15q、17q和18q增益作为独特事件。我们还检测了两种常见乳腺癌小鼠模型和我们的自发性肿瘤模型的病理类型，发现自发性肿瘤具有高水平Her2、Gata3和细胞角蛋白的乳腺癌特征。为了进一步研究乳腺癌患者和乳腺癌小鼠模型的免疫表型，我们通过免疫组织化学(IHC)检测IKKα和免疫细胞标志物的表达，发现IKKα主要表达在细胞质中。与MMTV-neu小鼠相比，IKKα△Itgax小鼠和乳腺癌患者的CD8+/CD4+细胞比值较高，而IKKα△Itgax小鼠和乳腺癌患者的CD163+/CD68+细胞比值较低。此外，TCGA数据显示，乳腺癌中IKKα水平与HER2表达相关。综上所述，我们的小鼠模型肿瘤具有乳腺癌的特征，更适合模拟乳腺癌的肿瘤微环境。为了进一步检查肿瘤微环境中的免疫细胞，特别是DC和T细胞，我们通过DEG分析评估了细胞簇的谱系特异性基因表达特征，发现经典树突状细胞(cDC)样群体增加了Ccr7, Ccl22和Fscn1的表达。编码Relb、Pten、Tcf4和Irf7的基因在肿瘤DC中下调，表明与正常乳腺DC相比，肿瘤DC损害了DC的发展。我们还发现，与正常乳腺DC相比，肿瘤DC中的抗原加工和递呈以及T细胞激活信号被下调。与正常乳腺组织相比，肿瘤T细胞中Tcf4的表达降低。与正常乳腺T细胞相比，来自肿瘤的T细胞凋亡信号上调，而激活的T细胞增殖和适应性免疫应答信号在肿瘤T细胞中下调，表明DC中IKKα缺乏损害了T细胞的活化。我们还使用Monocle从正常乳腺组织和肿瘤样本中以伪时间方式订购T细胞并生成轨迹图。来自肿瘤的T细胞位于前分支，并分叉成两个不同的分支。大多数正常乳腺T细胞存在于不同的分支S3。这些数据进一步表明，DC中IKKα的缺失诱导T细胞功能障碍，从而促进肿瘤免疫逃避。研究结果02为了进一步确定树突状细胞和T细胞相互作用(CCI)，我们计算了CCI分数，该分数代表了所有配体-受体对中所有亚簇对之间的通信概率。与肿瘤样本相比，正常乳腺样本中CCI更强，乳腺DC中Ccl、Cd86、Faslg和Ifn的表达也强烈上调。在与T细胞外向或传入相互作用的DC中也观察到类似的模式。我们还用流式细胞术研究了不同年龄的IKKα△Itgax小鼠的单核细胞、粒细胞和自然杀伤细胞。与野生型(WT)小鼠相比，老年IKKα△Itgax小鼠(20周龄)血液和脾脏中单核细胞的百分比均降低，肺部中单核细胞的百分比也显著降低。我们还发现，与WT小鼠相比，年轻和年老的IKKα△Itgax小鼠外周血和肺部的粒细胞比例显著增加。此外，老年小鼠DC中IKKα缺乏使外周血和肺中的自然杀伤细胞减少。然而，IKKα△Itgax小鼠脾脏中自然杀伤细胞的数量与WT小鼠相比无显著差异。这些数据表明，DC中IKKα的缺失会影响细胞群，为了深入了解IKKα△Itgax肿瘤和MMTV-neu肿瘤(GEO: GSE122336)之间的肿瘤浸润免疫细胞，我们从scRNA-seq数据中对CD45+细胞进行了分类，获得了6个簇。虽然这两组具有相似的免疫特征，但在IKKα△Itgax肿瘤中观察到巨噬细胞数量减少，T细胞浸润增加。此外，Pd1和Ctla-4在IKKα△Itgax肿瘤浸润的T细胞中表达上调。UMAP图发现DC特征的Ccr7, Ccl22和Cd68强烈表达。单片伪时间分析显示，MMTV-neu小鼠的T细胞处于细胞晚期状态，而IKKα△Itgax小鼠的巨噬细胞则处于原始细胞分化状态。这些结果进一步证实，与MMTV-neu小鼠相比，IKKα△Itgax肿瘤浸润T细胞和巨噬细胞处于原代细胞状态，这可能有助于肿瘤免疫逃逸。据我们所知，这是第一个显示免疫细胞遗传缺陷诱发实体瘤的病例。我们认为，确定DC的基因突变是否在表观遗传学上调控乳腺上皮细胞并最终导致上皮癌变是值得的。新的发现可能带来新的肿瘤预防和治疗策略。进一步的研究需要明确这种新型乳腺癌模型的分子机制，以及特定的肿瘤微环境特征，并确定其在IKKα△Itgax小鼠中乳腺细胞增生的特定时间和对HER2靶向治疗的敏感性。我们也相信我们的研究将为探索乳腺癌的免疫治疗提供一种新的小鼠模型，并通过促进DC中IKKα信号传导促进乳腺癌疫苗的开发。参考资料：https://www.nature.com/articles/s41421-023-00553-z注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。阅读原文特别声明本文为澎湃号作者或机构在澎湃新闻上传并发布，仅代表该作者或机构观点，不代表澎湃新闻的观点或立场，澎湃新闻仅提供信息发布平台。申请澎湃号请用电脑访问http://renzheng.thepaper.cn。+1收藏我要举报查看更多查看更多开始答题扫码下载澎湃新闻客户端Android版iPhone版iPad版关于澎湃加入澎湃联系我们广告合作法律声明隐私政策澎湃矩阵澎湃新闻微博澎湃新闻公众号澎湃新闻抖音号IP SHANGHAISIXTH TONE新闻报料报料热线: 021-962866报料邮箱: news@thepaper.cn沪ICP备14003370号沪公网安备31010602000299号互联网新闻信息服务许可证：31120170006增值电信业务经营许可证：沪B2-2017116© 2014-2024 上海东方报业有限公PyMT 诱导乳腺癌转基因小鼠模型的见解：重现人类乳腺癌体内进展,Oncogene - X-MOL
PyMT 诱导乳腺癌转基因小鼠模型的见解：重现人类乳腺癌体内进展,Oncogene - X-MOL
EN
注册
登录
首页
资讯
期刊
导师
问答
求职
发Paper
文献直达
高级搜索
期刊列表
搜索
当前位置：
X-MOL 学术
›
Oncogene
›
论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
PyMT 诱导乳腺癌转基因小鼠模型的见解：重现人类乳腺癌体内进展
Oncogene
(
IF
8
)
Pub Date : 2020-11-24
, DOI:
10.1038/s41388-020-01560-0
Sherif Attalla
1,
2
,
Tarek Taifour
2,
3
,
Tung Bui
2
,
William Muller
1,
2,
3
Affiliation
Department of Biochemistry, McGill University, Montreal, QC, H3A 1A3, Canada.
Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada.
Faculty of Medicine, McGill University, Montreal, QC, H3A 1A3, Canada.
乳腺癌是全球第二大癌症相关死亡病例。因此，了解决定乳腺癌进展、肿瘤微环境调节和转移（癌症相关死亡的主要原因）的关键事件非常重要。乳腺特异性多瘤病毒中T抗原过表达小鼠模型（MMTV-PyMT）于1992年首次发表，是癌症研究中最常用的基因工程小鼠模型（GEMM）。MMTV-PyMT 小鼠中出现的乳腺病变遵循与人类乳腺肿瘤相似的分子和组织学进展，使其成为癌症研究人员的宝贵工具，并有助于了解肿瘤生物学。在这篇综述中，我们将重点介绍一些关键研究，这些研究证明 PyMT 衍生的 GEMM 在了解乳腺癌进展、转移的分子基础方面的实用性，并强调其作为治疗发现的临床前工具的用途。
"点击查看英文标题和摘要"
Insights from transgenic mouse models of PyMT-induced breast cancer: recapitulating human breast cancer progression in vivo
Breast cancer is associated with the second highest cancer-associated deaths worldwide. Therefore, understanding the key events that determine breast cancer progression, modulation of the tumor-microenvironment and metastasis, which is the main cause of cancer-associated death, are of great importance. The mammary specific polyomavirus middle T antigen overexpression mouse model (MMTV-PyMT), first published in 1992, is the most commonly used genetically engineered mouse model (GEMM) for cancer research. Mammary lesions arising in MMTV-PyMT mice follow similar molecular and histological progression as human breast tumors, making it an invaluable tool for cancer researchers and instrumental in understanding tumor biology. In this review, we will highlight key studies that demonstrate the utility of PyMT derived GEMMs in understanding the molecular basis of breast cancer progression, metastasis and highlight its use as a pre-clinical tool for therapeutic discovery.
更新日期：2020-11-25
点击分享
查看原文
点击收藏
取消收藏
新增笔记
公开下载
阅读更多本刊最新论文
本刊介绍/投稿指南
https://www.nature.com/articles/s41388-020-01560-0.pdf
HTML
https://doi.org/10.1038/s41388-020-01560-0
HTML
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819848
全部期刊列表>>
学术期刊
行业资讯
全球导师
X-MOL问答
求职广场
网址导航
关于我们
帮助中心
客服邮箱：service@x-mol.com
官方微信：X-molTeam2
邮编：100098
地址：北京市海淀区知春路56号中航科技大厦
Copyright © 2014-2024 北京衮雪科技有限公司 All Rights Reserved
京ICP备11026495号-2
京公网安备 11010802027423号
down
bug
bug
Oncogenic Viruses and Breast Cancer: Mouse Mammary Tumor Virus (MMTV), Bovine Leukemia Virus (BLV), Human Papilloma Virus (HPV), and Epstein–Barr Virus (EBV) - PMC
Oncogenic Viruses and Breast Cancer: Mouse Mammary Tumor Virus (MMTV), Bovine Leukemia Virus (BLV), Human Papilloma Virus (HPV), and Epstein–Barr Virus (EBV) - PMC
Back to Top
Skip to main content
An official website of the United States government
Here's how you know
The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before
sharing sensitive information, make sure you’re on a federal
government site.
The site is secure.
The https:// ensures that you are connecting to the
official website and that any information you provide is encrypted
and transmitted securely.
Log in
Show account info
Close
Account
Logged in as:
username
Dashboard
Publications
Account settings
Log out
Access keys
NCBI Homepage
MyNCBI Homepage
Main Content
Main Navigation
Search PMC Full-Text Archive
Search in PMC
Advanced Search
User Guide
Journal List
Front Oncol
PMC5786831
Other Formats
PDF (245K)
Actions
Cite
Collections
Add to Collections
Create a new collection
Add to an existing collection
Name your collection:
Name must be less than characters
Choose a collection:
Unable to load your collection due to an error
Please try again
Add
Cancel
Share
Permalink
Copy
RESOURCES
Similar articles
Cited by other articles
Links to NCBI Databases
Journal List
Front Oncol
PMC5786831
As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with,
the contents by NLM or the National Institutes of Health.
Learn more:
PMC Disclaimer
|
PMC Copyright Notice
Front Oncol. 2018; 8: 1. Published online 2018 Jan 22. doi: 10.3389/fonc.2018.00001PMCID: PMC5786831PMID: 29404275Oncogenic Viruses and Breast Cancer: Mouse Mammary Tumor Virus (MMTV), Bovine Leukemia Virus (BLV), Human Papilloma Virus (HPV), and Epstein–Barr Virus (EBV)James S. Lawson,1,* Brian Salmons,2 and Wendy K. Glenn1James S. Lawson1School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, AustraliaFind articles by James S. LawsonBrian Salmons2Austrianova, Synapse, Biopolis, SingaporeFind articles by Brian SalmonsWendy K. Glenn1School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, AustraliaFind articles by Wendy K. GlennAuthor information Article notes Copyright and License information PMC Disclaimer1School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia2Austrianova, Synapse, Biopolis, SingaporeEdited by: Jianguang Ji, Lund University, SwedenReviewed by: Clement Adebamowo, University of Maryland, United States; Marianna De Camargo Cancela, Brazilian National Cancer Institute, Brazil*Correspondence: James S. Lawson, ua.ude.wsnu@noswal.semajSpecialty section: This article was submitted to Cancer Epidemiology and Prevention, a section of the journal Frontiers in OncologyReceived 2017 Oct 4; Accepted 2018 Jan 3.Copyright © 2018 Lawson, Salmons and Glenn.This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.AbstractBackgroundAlthough the risk factors for breast cancer are well established, namely female gender, early menarche and late menopause plus the protective influence of early pregnancy, the underlying causes of breast cancer remain unknown. The development of substantial recent evidence indicates that a handful of viruses may have a role in breast cancer. These viruses are mouse mammary tumor virus (MMTV), bovine leukemia virus (BLV), human papilloma viruses (HPVs), and Epstein–Barr virus (EBV-also known as human herpes virus type 4). Each of these viruses has documented oncogenic potential. The aim of this review is to inform the scientific and general community about this recent evidence.The evidenceMMTV and human breast cancer—the evidence is detailed and comprehensive but cannot be regarded as conclusive. BLV and human breast cancer—the evidence is limited. However, in view of the emerging information about BLV in human breast cancer, it is prudent to encourage the elimination of BLV in cattle, particularly in the dairy industry. HPVs and breast cancer—the evidence is substantial but not conclusive. The availability of effective preventive vaccines is a major advantage and their use should be encouraged. EBV and breast cancer—the evidence is also substantial but not conclusive. Currently, there are no practical means of either prevention or treatment. Although there is evidence of genetic predisposition, and cancer in general is a culmination of events, there is no evidence that inherited genetic traits are causal.ConclusionThe influence of oncogenic viruses is currently the major plausible hypothesis for a direct cause of human breast cancer.Keywords: breast cancer, oncogenic viruses, mouse mammary tumour virus, bovine leukemia virus, human papilloma virus, Epstein–Barr virus, multiple viral infectionsAim of This ReviewAlthough the risk factors for breast cancer are well established, namely female gender, early menarche and late menopause plus the protective influence of early pregnancy, the underlying causes of breast cancer remain unknown. The development of substantial recent evidence indicates that a handful of viruses may have a role in breast cancer. These viruses are mouse mammary tumor virus (MMTV), bovine leukemia virus (BLV), human papilloma viruses (HPVs), and Epstein–Barr virus (EBV—also known as human herpes virus type 4). Each of these viruses has documented oncogenic potential.The aim of this review is to inform the scientific and general community about this recent evidence.It is helpful to consider this evidence in the context of past studies. It is also helpful to consider the potential role of these four oncoviruses in a single review because there is emerging evidence that one or more of them may collaborate.IntroductionWe have used an extension of the classic Hill criteria to review the evidence (1). These criteria are (i) strength of association (the odds ratio with the higher the strength of association between a causal agent the more likely an association), (ii) consistency (the confirmation of findings in repeated studies conducted by different researchers in different locations and at different times), (iii) specificity (the more specific the relationship between a causal agent and a disease the more probable there is an association), (iv) temporality (the time sequence where an event such as infection with a causal agent precedes a specific disease), (v) biological gradient (response to different concentrations or length of exposure to the causal agent) (vi) plausibility (conclusions drawn from previous evidence such as the oncogenic capacity of an infectious agent), (vii) coherence (overall the evidence is consistent), (viii) experimental evidence (the most valuable is a demonstration that the disease will not develop if the presumed cause is removed, such as use of an effective preventive vaccine), and (ix) analogy (an example is the proven cause of cancer by viruses in animals which may have parallels in humans). With respect to viruses, additional causal criteria to the Hill criteria are (i) viral genetic material is present in cancer tissues but rarely in normal tissues, (ii) the virus is capable of transforming normal cells into malignant cells, (iii) the viral oncogenic mechanism is understood, and (iv) the means of viral transmission has been identified. There are differences in the importance of each criterion. With respect to viruses and cancer the identification of viral genetic material and a significant odds ratio between cancer and normal tissues are of special importance.The development of conclusive evidence for a viral cause of breast cancer is extremely difficult because the proportion of viral nucleic acids in a cancer sample is usually very small when compared with host-derived genetic material. MMTV and BLV are retroviruses. Retroviral genomes rarely exceed 10–12 kb, and hence constitute a minor fraction of the genome of the infected host cell. The infected cell type may constitute only a small fraction of the sample, and the infected cells may contain a relatively low number of viral genome copies (2). HPVs and EBV are DNA viruses. The viral load of high risk for cancer HPVs is 2,000-fold less in breast cancer when compared with cervical cancer (3). Although these viruses can be detected by whole-genome sequencing, amplification techniques such as nested polymerase chain reaction (PCR) can be required for their successful identification. However, because of these problems the outcomes of PCR can be inconsistent and even falsely negative. It can also be argued that these viral loads are so low that they may not be oncogenic.Techniques Used to Implicate Viruses in Breast CancerThe techniques used for the identification of viruses in breast and other cancers are of fundamental importance to the validity of studies aimed at determining viral causes of cancer. These techniques include (i) various types of PCR—standard PCR which is based on extracts of DNA from target tissues and cannot be used to identify the location of viral gene sequences in specific cell types, and in situ PCR which can identify viral gene sequences in specific cells, (ii) in situ hybridization which can identify viral gene sequences in specific cells but which is much less sensitive than PCR amplification techniques, (iii) immunohistochemistry which can be used to identify viral proteins, and (iv) massive genome sequencing which can be used to identify specific viral gene segments but does not appear to be as sensitive as PCR. Because of its sensitivity, PCR remains as the most commonly used technique but is notoriously subject to contamination which can lead to false positive results. Joshi and Buehring have reviewed the techniques that have been used in studies of MMTV, HPVs and EBVs in breast cancer (4). They have shown there is considerable variation in the quality of these studies and have suggested a number of criteria which should be used to assess the validity of results. These criteria include (i) the use of in situ molecular methods (in situ PCR) either initially or as confirmation of results based on standard PCR so as to identify the cell type positive for the virus and to avoid contamination, (ii) the use of in situ hybridization tests, and (iii) the use of normal control breast tissues from women with no history of breast cancer and not from normal tissues adjacent to breast tumors.In this review, we have used published meta-analyses as one basis for the selection of studies listed in the tables. While we did not identify any biases in these meta-analyses, we have only included in the tables studies which report results which include adequate controls and which meet the criteria outlined above.Mouse Mammary Tumor VirusSome background is helpful to place the evidence in context. While working at the Jackson Laboratory in Maine in 1936, John Bittner discovered a cancerous agent, which he called a “milk factor,” which could be transmitted by milk from mouse mothers with mammary tumors to their mouse pups, who as adults, later developed mammary tumors (5). Graff et al., working in New York in the post—World War II years, identified viral particles in mouse milk which they showed could cause mammary cancer when injected intraperitoneally into laboratory strains of mice (6). In 1966, Peter Duesberg and Phyllis Blair, working at the University of California at Berkeley, identified this virus as a retroviral RNA virus, similar to other RNA tumor viruses and which has become known as MMTV (7). The biology of MMTV has been intensively studied and is the proven cause of mammary cancers in wild (feral) and experimental mice (8). MMTV has been identified in a number of different organs in the mouse including the mammary glands, the prostate, salivary glands, and the lymphatic system (8). MMTV has also been identified in several different mammal species including humans, dogs, cats, and monkeys (9).Mouse mammary tumor virus became an obvious suspect as a causal agent in human breast cancer and financial resources from the President Richard Nixon war on cancer were allocated to research in this field. A major breakthrough came with the identification of RNA in human breast cancer that was homologous to MMTV RNA (10). This observation was confirmed during the next decade at the DNA level (11–13). However, it was difficult to distinguish MMTV gene sequences from those of the human endogenous retrovirus (HERV). HERV gene sequences are very similar to MMTV and may be the remnants of MMTV viruses that have become integrated into the human genome over millennia (14). This problem was overcome by the Beatriz Pogo group working in the Mount Sinai Medical Center in New York, by their identification of MMTV envelope gene sequences which were unique to MMTV (15). Their work lead to a resurgence of interest in MMTV and human breast cancer. The likely lifecycle of MMTV in humans appears to be very similar to the lifecycle of MMTV in mice. This offers an almost unique animal model which has allowed investigators to follow specific lines of enquiry.Identification of MMTV in Human Breast CancerUsing hybridization with cloned MMTV DNA techniques (16–18), Callahan et al., Westley and May, and May and Westley, identified related sequences in human breast cancer cells. Using similar hybridization methods, Szakacs and Moscinski (13) identified the entire provirus of MMTV with a typical structure of a retrovirus [long terminal repeat (LTR), group specific antigen (gag), capsid region, polymerase (pol), reverse transcription region, and envelope (env) in 7 (13%) of 52 human breast cancers]. The identification of MMTV sequences by hybridization techniques in these studies is important because of the later controversies related to the use of PCR techniques.With respect to the review of MMTV in human breast cancer, the publications included in a meta-analysis by Wang et al. supplemented by more recent publications were considered and included in Table Table11 (19). Only case control studies with adequate controls are included. The criteria for inclusion in this meta-analysis were (i) studies had to use PCR-based techniques to detect regions of the MMTV envelope gene that have low homology to known HERVs in tissues and (ii) only studies on breast cancer in females. The results indicate there is a 15-fold higher prevalence of MMTV env sequences in human breast cancers when compared with non-cancer controls. It should be noted that these studies are heterogeneous and accordingly this meta-analysis cannot be regarded as definitive. Despite this reservation, MMTV env gene sequences were identified in breast cancers but not normal breast controls by in situ PCR in three of the studies in Table Table11 (20–22). Several studies which did not identify MMTV gene sequences have been omitted from Table Table11 because of inadequate methods as judged by the criteria of Joshi and Buehring (4).Table 1Identification of MMTV sequences in breast cancer and comparison non-cancer breast specimens (case–control studies).ReferenceLocationDiagnosisNon-cancer controlsSpecimen identification techniqueMMTV positive/total cancer specimensMMTV positive/total non-cancer specimensWang et al. (15)USInvasiveNormal breastFrozen PCR121/314 (38.5%)2/107 (2%)ISHEtkind et al. (23)USInvasiveNormal breastFrozen PCR27/73 (37%)0/35 (0%)ISHMelana et al. (24)USInvasiveAdjacent normal breastFormalin PCR32/106 (30%)1/106 (1%)ISHMelana et al. (25)ArgentinaInvasiveFrozen PCR23/74 (31%)1/10 (10%)Ford et al. (26)AustraliaDCISBenignFormalin PCRDCIS 5/19 (26%)2/111 (2%)InvasiveIDC 14/26 (54%)Ford et al. (20)AustraliaInvasiveNormalFormalin. in situ PCR45/144 (31%)0/20 (0%)DCISISH2/8 (25%)Zammarchi et al. (27)ItalyInvasiveAdjacent normal breastFrozen PCR13/43 (30%)1/8 (12.5%)MicrodissectionBindra et al. (28)SwedenInvasiveAdjacent normal breastFrozen PCR0/18 (0%)0/11 (0%)Hachana et al. (29)TunisiaInvasiveAdjacent normal breastFrozen PCR17/122 (14%)0/122 (0%)Mazzanti et al. (21)ItalyDCISNormal cosmeticFormalin PCR, in situ PCR, ISH40/49 (82%)0/20 (0%)Invasive7/20 (35%)Lawson et al. (30)AustraliaDCISNormal cosmeticFormalin PCR, in situ PCR33/74 (45%)0/29 (0%)InvasiveGlenn et al. (22)AustraliaInvasiveNormal cosmeticFrozen PCR: in situ PCR39/50 (78%)13/40 (33%)Slaoui et al. (31)MoroccoInvasiveAdjacent normal breastFormalin PCR24/57 (42%)6/18 (33%)Cedro-Tanda et al. (32)MexicoInvasiveAdjacent normal breastFrozen57/458 (12%)72/458 (16%)PCRReza et al. (33)IranInvasiveAdjacent normal breastFormalin12/100 (12%)0/100 (0%)DCISPCRNaushad et al. (34)PakistanInvasiveNormalFormalin PCR83/250 (29%)0/15 (0%)Shariatpanahi et al. (35)IranInvasiveBenignFormalin PCR19/59 (32%)3/59 (5%)Open in a separate windowDCIS, ductal carcinoma in situ; PCR, polymerase chain reaction; ISH, in situ hybridization; MMTV, mouse mammary tumor virus.There are geographical differences in the prevalence of MMTV in mice which may influence the prevalence of MMTV in humans (36). The higher the prevalence of one species of house mouse, Mus domesticus, the higher the prevalence of human breast cancer (36). The prevalence of MMTV positive breast cancers in Western countries is broadly consistent between 30 and 40% and in Asian countries between 10 and 20% (36). These differences may, in part, be due to the differences in exposure to MMTV in mice (36).There are wide variations in the identification of MMTV in breast cancers from the same countries. For example, the identification of MMTV in breast cancers in Mexico varied from nil to 16% and in Iran nil to 12%. By comparison the outcomes of multiple studies in the US, Italy, and Australia are broadly similar. It is likely that some of these differences are due to the technical difficulty of identifying MMTV sequences by PCR. We have recently shown that the outcomes of PCR used to identify MMTV can differ despite the use of the same specimens (37). However, PCR is the most sensitive technique available for the detection of low level viral infections and the outcomes should not be discounted because of these difficulties. In some of the published studies the methods are clearly inadequate as for example the omission of a positive control or the failure to achieve a positive control outcome (38–40). These studies have not been included in Table Table11.It should be noted that hybridization techniques have also been used to successfully confirm the outcome of PCR amplification techniques in 5 of the 17 studies in Table Table1.1. In situ PCR techniques were also used which confirmed the outcomes of standard PCR in two studies. In situ PCR is less likely to give false negative and positive outcomes. It should also be noted that the identification of MMTV were similar whether PCR primers based on envelope gene or LTR gene MMTV sequences are used (41). MMTV encodes a characteristic dUTPase in the gag gene and future confirmatory studies using primers in this region might be useful (42).Overall, the much higher prevalence of MMTV positive identification in breast cancers when compared with non-cancerous breast tissues is suggestive of a role for MMTV in a subset of human breast cancers.Whole-Genome SequencingThe identity of MMTV in human breast cancers has been confirmed by whole-genome sequencing (43, 44). However, MMTV sequences were identified in only 3 of over 800 breast cancer specimens from The Cancer Genome Atlas (TCGA). This is an indication that PCR is much more sensitive than whole-genome sequencing (2).The almost complete genome of MMTV in human breast cancers has been identified with 84–99% homology to MMTV in mouse breast cancers (45, 46). Breast cancer cells produce MMTV-like viral particles that are similar to the mouse virus with sequence homologies 85–95% the same as MMTV (45). Nucleotides, gene sequences and number of base pairs in the MMTV genome are virtually identical in both mouse and human breast cancers (45–47).SpecificityMouse mammary tumor virus is unlikely to be uniquely specific to breast cancer as it has been identified in several additional cancers including lymphoma, prostate, liver, and endometrial cancer (48–50). There is no evidence to determine whether MMTV is causal in these cancers.Breast Cancer-Related Gene ExpressionThe same cancer-related genes are deregulated in both MMTV-associated mouse and human breast cancer (51, 52). These genes are mainly associated with cell proliferation.MMTV Proteins in Human Breast CancerThe MMTV envelope proteins (gp 36 and gp 52) have been identified in primary cultures of human breast cancer cells which confirm earlier findings (53–55).MMTV Biological GradientThe MMTV viral load appears to increase as human breast cancer progresses but falls in late stage invasive breast cancer (20, 21). In a study based on Italian women, MMTV was not identified in normal breast tissues from cosmetic breast surgery, but MMTV was identified in increasing prevalence in 27% of breast hyperplasias and 80% of non-invasive ductal carcinoma in situ but less prevalent in invasive ductal carcinomas which were 35% MMTV positive (21).SerologySerological-based studies of MMTV in human breast cancer have produced conflicting outcomes. Older studies identified serological responses to MMTV (56–58). Indeed, Dion et al. reported that laboratory workers exposed to MMTV showed serological responses to the MMTV env (gp52 and gp34) and gag (p12, p18, p28) proteins (58). However, later studies based on more modern methods did not achieve clear outcomes (59). Although 30% of the sera from women with breast cancer showed some serological reactivity against MMTV virus, none could be immunoprecipitated using purified MMTV proteins (59).Temporality: MMTV Infection and Subsequent Breast Cancer Time SequenceFive of six Australian women with MMTV positive benign breast biopsy tissues 1–11 years later developed MMTV positive breast cancer (37). The prior benign and later breast cancer specimens were from the same individual patients (37).Superantigen (SAg) ExpressionMouse mammary tumor virus SAgs play an essential role in MMTV-associated mouse mammary tumors (60). MMTV infection of antigen presenting cells such as B lymphocytes and dendritic cells leads to the expression of virus SAgs which in turn stimulate T cells to produce cytokines that encourage the proliferation of infected B lymphocytes. MMTV is then conducted throughout the body by these lymphocytes which facilitate the entry of MMTV into its target organ (the breast or other organs). MMTV SAg is highly expressed in MMTV-associated human breast cancer and may have a similar role in humans as it does in the mouse (61). Human T cells respond to MMTV SAg (62).Hormone ResponseMammary tumors in mice are hormone dependent (63–65). In humans, MMTV hormonal response elements in breast cancers appear to promote cell growth as they do in the mouse system (66).MMTV Capacity to Infect Human Breast Epithelial CellsMouse mammary tumor virus is capable of infecting human breast cells in culture and can randomly integrate its genomic information into the genome of the infected cells (67–69). When MMTV is integrated into the human genome the flanking sequences are of human and not mouse origin which is an indication of an exogenous infection rather than contamination (70). Integration of MMTV into the human genome appears to be random and in multiple locations as has been previously observed in mice (70).Etkind et al. (71) identified a family in which the father, mother and daughter living together, all developed breast cancer. Each of the three breast cancers contained env gene sequences that were at least 98% homologous to the MMTV env sequences found in laboratory mouse strains. This provides support for an infective virus transmission.MMTV TransmissionMouse mammary tumor virus has been identified in human milk from normal lactating mothers (72). The prevalence of MMTV in human milk is significantly higher among women who are at greater than normal risk of breast cancer (73). MMTV gene sequences have been identified in human saliva (74). MMTV gene sequences are present in saliva in 27% of normal children, 11% of normal adults and 57% of women with breast cancer (74). This suggests saliva as a route in inter-human infection. MMTV gene sequences have been identified in dogs and cats (9, 75). Women with companion dogs are at twice the expected risk of breast cancer (76). In addition the biological and histological characteristics of canine mammary tumors are very similar to human breast cancer (77). These observations are suggestive of transmission of MMTV in dog saliva to humans.Identification of MMTV in Other AnimalsMouse mammary tumor virus is the proven cause of mammary cancers in wild (feral) mice (8). MMTV-like gene sequences have been identified in 20% of mammary tumors in dogs and 33% of cats (75). Gene sequences with high homology to MMTV have been identified in rhesus monkeys and cats although the tissues studied were not mammary tumors (9).HistopathologyThe histopathology in the early stages of MMTV-associated mouse and human breast cancers are very similar and in some cancers are virtually identical (30, 78). However, these characteristics are not sufficiently different from several other cancers in humans, such as basal cell skin carcinomas, to act as diagnostic criteria. The histological characteristics of breast cancer in wild and experimental mice were studied in detail by Thelma Dunn during and after the 1940s (79). Over 90% of mouse mammary tumors in wild (feral) mice are adenocarcinomas. Dunn classified these tumors as types A and B. The breast glands are present in type A. Type B, the most common type, is characterized by dense round cancer cells without glands.Wellings made the first observation that some human breast cancer specimens had similar histopathology characteristics to MMTV-associated mouse breast cancers (80). However, there is a belief that MMTV-associated mouse breast cancers do not resemble human breast cancers. This belief may be based on the observations made by Hamilton in 1974 (81). At that time most observations were made at a late stage in the development of breast cancer. Hamilton described human invasive ductal breast carcinomas which were characterized by streams of elongated malignant cells surrounded by dense connective tissues which were clearly different from the histopathology of mouse breast cancers. This may explain Hamilton’s conclusions as Wellings observations were based on the early proliferative stages of mouse breast and human breast cancers whereas Hamilton’s conclusions were made on the late invasive stage of human breast cancer (80, 81). The histopathology of early proliferative stages of human breast cancer is very different from late stage human breast cancer.Mechanisms of MMTV Oncogenesis in Human Breast CancerEven though MMTV has been classified as a non-acutely transforming retrovirus, there is experimental evidence that proteins expressed by the MMTV envelope gene are capable of malignantly transforming normal human breast epithelial cells (82). However, the mechanisms by which MMTV may cause cancer are far from clear. It has been experimentally demonstrated that integration of MMTV proviral DNA into the target genome near one or more of the proto-oncogenes such as Wnt-1 and Fgf are associated with the development of mouse mammary tumors (83). However, integrations in the vicinity of multiple proto-oncogenes seem to be required, together with other genetic insults as well as predisposing genetic mutations (84). The insertion of the MMTV enhancers in the vicinity of proto-oncogenes results in their deregulated expression which stimulates cell growth (84). It is of interest that Wnt-1 expression is higher in specimens of MMTV env-positive ductal carcinoma in situ and invasive ductal carcinoma, than in MMTV env-negative specimens (30). However, if MMTV is causing human breast cancer like it does in mice, then MMTV DNA should be readily detectable in tumors since they are derived by clonal outgrowth of one (or a few) originally infected cells that carry an integrated provirus near a cellular oncogene. Moreover, most MMTV-induced mammary tumors seem to contain 10 or more proviral integrations and it is thought that MMTV-induced tumors arise when these multiple integrations occur in a single cell (85). However, the relatively low levels of MMTV that are detected in human breast cancers suggest that the virus is affecting oncogenesis by mechanisms other than enhancer insertion.Mouse mammary tumor virus envelope proteins have been proposed to be involved in tumorigenesis (86, 87). MMTV envelope protein overexpression can lead to morphological changes in normal 3-dimensional mouse breast cell cultures (86). As noted previously, the envelope proteins of Jaagsiekte Sheep Retrovirus which like MMTV is a beta retrovirus, can directly transform cells (88).Mouse mammary tumor virus-encoded proteins (such as Rem, Sag, Naf) or as yet uncharacterized proteins analogous to those of other complex retroviruses such as Tax may also have a role in breast cancer (87). Further, it has been shown that MMTV, like some other retroviruses, can influence infected host cell miRNA, enhancing the expression of members of the oncogenic mi RNA cluster, mi-17–92 (89). There is also the intriguing possibility that MMTV and HERVs may interact and thus also play a role (86).It is also conceivable that MMTV infection activates a latent human DNA virus such as EBV or human papillomavirus (HPV)—both of which are candidate viruses associated with human breast cancer, in an analogous fashion to the way that human immunodeficiency virus has an indirect role in Kaposi’s sarcoma (87).Apolipoprotein B editing complex (APOBEC) family genes encode deaminase enzymes that edit DNA and/or RNA sequences thus playing a central role in the control of virus infections, including retroviruses (90). APOBEC enzymes normally function in innate immune responses, including those that target retroviruses, suggesting links between mutagenesis, immunity and viral infection in cancer development. In mouse models, APOBEC3 has been shown to inhibit MMTV infections and viral replication and to restrict milk borne MMTV virions (90–92). Abnormal expression of APOBEC3B may reduce its protective effects against MMTV. Inactivating mutations and deletions in APOBEC3B are also thought to play a role in breast cancer development. Aberrant expression of APOBEC3B has also been shown to be induced by DNA viruses such as HPV, specifically in breast cancer (93, 94). Moreover, a deletion polymorphism in the APOBEC3B gene cluster on chromosome 22 is associated with elevated breast cancer risk and a specific APOBEC mutation pattern has been described in a number of cancers, including breast cancer, suggesting a functional link with cancer development (95, 96). This mutation pattern is linked to APOBEC3B expression specifically in breast cancer and leads to DNA damage that could select TP53 inactivation, thereby resulting in tumor heterogeneity (97). Recently, it has been shown that there is a significant increase in APOBEC-mediated mutagenesis in HER+/HER2 metastatic breast tumors when compared with early stage primary breast cancer (98). Taken together, these studies suggest that the APOBEC family and particularly APOBEC3B may play a central role in the early stages of breast cancer induction. Additional studies are required to demonstrate a link between MMTV, APOBEC, and breast cancer.Analogy between MMTV-Associated Human Breast Cancer and MMTV-Associated Mouse Mammary TumorsThe biology of MMTV in humans appears to be very similar to MMTV in mice (8). The evidence related to MMTV-associated human breast cancer and MMTV induced mouse mammary tumors, is remarkably similar. The key evidence is summarized in Table Table22.Table 2Comparative evidence.Mouse mammary tumor virus (MMTV)Mouse mammary tumorsHuman breast cancerMMTV nucleotide and gene sequencesComplete MMTV genome of 9,900 base pairs identified (99–101)Almost complete MMTV genome identified with 84–99% homology with mouse MMTV genome (45, 46). MMTV identification confirmed by whole-genome sequencing (45)MMTV virus particlesMMTV virus particles visualized in mouse milk (99)MMTV virus particles visualized in human milk (99)MMTV breast cancer prevalenceMMTV identified globally in mouse mammary tumors (36)MMTV-like virus identified globally in breast cancers (36)Cancer-related gene expressionSame cancer genes deregulated in mouse mammary tumors and human breast cancer (51, 52)Same cancer genes deregulated in mouse mammary tumors and human breast cancer (51, 52)Temporality—MMTV infection time sequenceMMTV present in 0–50% of wild mice. 1% develop breast cancer (102, 103)MMTV present in prior benign breast later breast cancer (37)MMTV protein expressionMMTV proteins expressed (8, 104)MMTV proteins expressed (53)MMTV superantigen expression (SAg)MMTV SAg plays an essential role in MMTV mouse breast cancer (60)Human T cells respond to MMTV SAg (61). MMTV-like SAg identified in human breast cancer (61)MMTV serum antibodiesPositive serological response to MMTV (105)Positive serological response to MMTV (56–58). Serology not confirmed (59)Hormone responsivenessMouse mammary tumors hormone dependent (8)MMTV hormonal response elements promote cell growth (66)MMTV transmissionMMTV transmitted by mouse milk to pups, which develop mouse mammary tumors as adult mice (8). MMTV present in mouse salivary gland—possible route of transfer (106)Potential transmission by human milk and human saliva (72–74)Infection experimentsExogenous MMTVs target dendritic cells and B lymphocytes in intestinal lymphocytes and mouse mammary cells (8)MMTV infects intestinal lymphocytes, human breast cells and randomly integrates into human genome (67, 68, 70, 107)MMTV morphologyClassical MMTV mammary tumor morphology—Dunn types A and B (79)Some MMTV positive breast cancers similar to MMTV positive mouse mammary tumors (30, 78)Open in a separate windowMMTV-associated human breast cancer and MMTV-associated mouse mammary tumors.In mice MMTV is spread by the milk of infected mouse mothers and is acquired by suckling pups (8).Ingested MMTV enters T and B cells located in Peyer’s patches of the gastrointestinal tract of infected mouse pups. This spread of MMTV infection requires activation of T and B lymphocytes by the viral Sag. Sag activation allows the virus to amplify in lymphocytes prior to transmission of the virus to mammary epithelial cells. Ultimately the virus is transported by infected lymphocytes to the mammary glands where oncogenic transformation takes place (8).In humans, MMTV infects lymphocytes located in the intestine and randomly infects and integrates into the human genome located in normal breast epithelial cells (67–70, 107).Bovine Leukemia Virus and Breast CancerBovine leukemia virus is a delta retrovirus which is closely related to the human T cell leukemia virus 1 (108). It is the cause of leukemia in beef and dairy cattle. BLV has typical retroviral genome regions: LTR (promoter region), gag (group specific antigen, capsid region), pol (polymerase, reverse transcription region, which synthesizes a DNA copy of the BLV RNA genome), and env (envelope). However, unlike other oncogenic retroviruses, delta retroviruses have an additional region, tax (trans-activating region of the X gene), which has regulatory functions and is oncogenic to host cells. Tax causes malignant transformation by inhibition of DNA repair and disruption of cellular growth control mechanisms.Clinical leukemia develops in less than 5% of infected cattle, however, BLV-infected lymphocytes are also found in the blood and milk of sub clinically infected cows (108). BLV-infected cattle herds are found worldwide. In the USA, approximately 38% of beef herds, 84% of all dairy herds, and 100% of large-scale dairy operation herds are infected (109). In Argentina, which has a major cow’s milk and beef industry, a majority of the herds are infected with BLV (110). In contrast, because of the culling of infected cattle, BLV infections have been virtually eliminated in Australian and European cows (111). However, virtually all Australians have consumed cow’s milk or milk-based products such as ice cream and cheese on a regular basis since infancy and many would have been exposed to BLV-infected milk. It is possible that any oncogenic influences of BLV may take decades to develop into breast cancer and accordingly no reduction in breast cancer prevalence can be anticipated for many years.Identification of BLV in Human Breast TissuesBovine leukemia virus gene sequences have been identified by PCR in human breast cancers (112–115). In a case control study based on PCR, 67 (59%) of 114 US breast cancers were positive for BLV when compared with 30 (29%) of 104 normal breast controls—odds ratio of 3 (114). There was a similar prevalence pattern in a recent study of breast cancer in a series of women from Texas (116). Of interest in this study was the increase in prevalence of BLV in benign breast tissues (19.6%), pre-malignant breast tissues (34%) and malignant breast tissues (57.4%) (116). In a case control study also based on PCR, 40 (80%) of 50 Australian breast cancers were BLV positive when compared with 19 (41%) of 46 normal controls—odds ratio 4.7 (115). There is an anecdotal report of BLV being able to infect human cells but these were of neural origin (117). The data in these studies are shown in Table Table33.Table 3Bovine leukemia virus and human breast cancer.ReferenceBreast specimensDiagnosisNon-cancer controlsIdentification techniqueBovine leukemia virus positive breast cancer (%)Bovine leukemia virus positive non-cancer controls (%)Giovanna et al. (112)ColumbiaInvasive breast cancersBenign breast tissuesStandard PCR19/53 (36%)24/53 (45%)Buehring et al. (114)USInvasive breast cancersNormal breast tissuesIn situ PCR67/114 (59%)30/104 (29%)Buehring et al. (115)AustraliaInvasive breast cancersBenign breast tissuesIn situ PCR40/50 (80%)19/46 (41%)Baltzell et al. (116)USInvasive breast cancersBenign breast tissuesIn situ PCR35/61 (57%)20/103 (20%)Gillet et al. (118)USInvasive breast cancersNormal next to breast cancerWhole-genome sequencing0/510/19Open in a separate windowBovine leukemia virus capsid proteins have been identified in the serum of 191 (74%) of 257 healthy human adults (119).Contrary to these positive findings, Zhang et al. (120) did not identify BLV by PCR in Chinese breast cancers. However, the methods used do not appear to be adequate (121).Using whole-genome sequencing methods BLV was not identified in 51 breast cancers (118). The reason for the negative outcome based on whole-genome sequencing is not clear. A plausible reason is that whole-genome sequencing techniques are not as sensitive as amplification techniques such as PCR and the authors were assuming that BLV would have to be present in all cells of the tumor and this may not be the case (2). BLV gene sequences were identified by PCR techniques in human breast cancer in the studies by Giavanni et al. (112) and Buehring et al. (113) which is an indication that their observations are sound.Temporality: BLV Infection and Subsequent Breast Cancer Time SequenceBovine leukemia virus was identified in 23 (74%) of 31 benign breast biopsy tissues 3–10 years before the development of BLV positive breast cancers in the same patients (115). The prior benign and later breast cancer specimens were from the same individual patients (115).EpidemiologyBovine leukemia virus and BLV-infected cells are present in colostrum and milk of most infected cows (108). This is the most likely means of transmission from cows to humans. There is a striking geographical correlation between breast cancer mortality and milk and bovine meat consumption (122). Zur Hausen and de Villiers have demonstrated consistent correlations between the consumption of bovine meat and cow’s milk and the prevalence of breast cancer (122). Their data is based on comparisons between countries. Countries such as the US, the United Kingdom, Australia, and Germany each have high consumption of bovine meat and milk and high prevalence of breast cancer. Countries such as India, Japan, Korea, and China have low consumption of bovine meat and milk and low prevalence of breast cancer. The relevant data is shown in Table Table4.4. Women with lactose intolerance and who have a low consumption of milk and dairy products, have a significantly lower risk of breast cancer than other women and other family members (123). In a Swedish based study by Ji et al., 22,788 individuals with lactose intolerance and who consumed only small quantities of cow’s milk and other dairy products, had a 20% lower prevalence of breast cancer when compared with 69,922 siblings and parents (123). Although this might indicate the involvement of a virus transmitted in milk or dairy products as hypothesized by zur Hausen and de Villiers (122), there are additional possible explanations. These include (i) caloric restriction which is associated with a lower incidence of breast cancers (124), (ii) the presence of growth factors in milk fats which may be associated with breast cancer risk (125), (iii) alterations to the human gut microbiome by avoidance of milk consumption and which may influence the development of cancers (126), and (iv) the potentially protective effects of dietary factors such as consumption of plant milk, including soy and rice milks, which are often consumed by women with lactose intolerance (127).Table 4Breast cancer mortality, incidence, milk, and bovine meat consumption high- and low-risk countries (per 100,000 women age adjusted) (2, 12, 128).CountryBreast cancer mortality/100,000 womenMilk (kcal/person/day)Bovine meat (kcal/person/day)Argentina19.9187347United Kingdom17.121565Germany15.512837United States14.9197115Australia14.0186126Japan9.88428South Korea6.12046Open in a separate windowHigh-Risk Human Papilloma Viruses and Breast CancerIdentification of High-Risk HPVs in Human Breast TissuesHigh-risk HPVs are the cause of cervical cancer and have a role in head and neck and other cancers. The HPV viral load in breast cancer is extremely low when compared with HPV in cervical cancer (3). As a consequence, identification of HPV in breast tumors is difficult whether by amplification techniques such as PCR or whole-genome sequencing. The low viral load is the likely reason that several laboratories have not been able to detect HPV. On the other hand HPV gene sequences have been identified in breast tumors in over 40 studies conducted in 20 countries (129, 130). With respect to the review of HPVs in human breast cancer, the publications included in the meta-analyses by Bae et al. and Choi et al. supplemented by more recent publications have been considered and included in Table Table55 (129, 130). These data indicate that high-risk HPVs are fourfold more prevalent in breast tumors when compared with non-cancer controls.Table 5Identification of high-risk HPVs in breast cancer and benign or normal breast controls in case control studies.ReferenceCountryIdentification techniqueHPV-positive breast cancers/total breast cancersHPV-positive non cancer breast/total non-cancer breast controlsMain HPV typesYu et al. (131)Japan/ChinaPCR18/52 (35%)0/15 (0%)18, 33Damin et al. (132)BrazilPCR25/101(25%)0/41 (0%)16, 18Tsai et al. (133)TaiwanPCR8/62 (13%)2/42 (5%)Choi et al. (134)KoreaPCR8/123 (7%)0/31 (0%)16, 18, 58Gumus et al. (135)TurkeyPCR37/50 (74%)9/16 (56%)18, 33He et al. (136)ChinaPCR24/40 (60%)1/20 (5%)16de Leon et al. (137)MexicoPCR15/41 (37%)0/43 (0%)16, 18Heng et al. (138)AustraliaIS PCR8/26 (31%)3/28 (11%)16, 18PCRHerrara-Goepfert et al. (139)MexicoPCR6/60 (10%)7/60 (12%)16Mou et al. (140)ChinaPCR4/62 (6%)0/46 (0%)16, 18Chang et al. (141)ChinaPCR0/48 (0%)3/30 (10%)6, 11Sigaroodi et al. (142)IranPCR15/43 (35%)1/40 (3%)16, 18Frega et al. (143)ItalyPCR9/31(29%)0/12 (0%)16, 18Glenn et al. (22)AustraliaIn situ PCR25/50 (50%)8/40 (20%)16, 18PCRLiang et al. (144)ChinaISH48/224 (21%)6/37 (16%)16, 18, 33, 58Ahangar-Oskouee et al. (145)IranPCR22/65 (34%)0/65 (0%)16Ali et al. (146)IraqISH60/129 (47%)3/41(7%)16, 18, 33Manzouri et al. (147)IranPCR10/55 (18%)7/51 (14%)16Peng et al. (148)ChinaPCR2/100 (2%)0/50 (0%)18Fu et al. (149)ChinaPCR25/169 (15%)1/83 (1%)58ISHLi et al. (150)ChinaPCR3/187 (2%)0/92 (0%)6, 16, 18Wang et al. (151)ChinaISH52/146 (36%)3/83 (4%)16, 18, 58Delgado-García et al. (152)SpainPCR131/251 (52%)48/186 (26%)16, 31, 39, 51, 59Salman et al. (153)United KingdomPCR46/110 (42%)1/11 (2%)16, 31, 33, 39Naushad et al. (34)PakistanPCR45/250 (18%)0/15 (0%)Open in a separate windowPCR, polymerase chain reaction; ISH, in situ hybridization; HPV, human papilloma virus.The prevalence of high-risk HPV-positive breast cancers varies between 0 or 2% in some Chinese Provinces to 86% in the US (118, 122). HPV types 16 and 18 are the most prevalent in breast cancer, however, HPV 33 and 58 are common in China and Japan (129, 130). Meta-analyses indicate that infection with high-risk HPVs is associated with an increased risk of breast cancer with an overall odds ratio of 5.4 (129, 130). However, there are marked differences between countries in the prevalence of different types of high-risk HPVs in breast cancer. The prevalence of HPV types and associated risk of breast cancer, varies between countries and regions within countries.High-risk HPVs have been identified in the SK-BR-3 breast cancer cell line (165). High-risk HPVs have been identified in invasive breast cancers using whole-genome sequencing (166). HPV-positive koilocytes have been identified in breast cancers (167). Koilocytes are HPV infected epithelial cells with characteristic haloes surrounding a small nucleus. HPV E6 and E7 oncoproteins have been identified in breast cancer (138), however, there is a low level of transcription of these oncoproteins (168).TemporalityHigh-risk HPVs have been identified in benign breast tissues which subsequently developed HPV-positive breast cancer 1–11 years later in the same patients (166). The prior benign and later breast cancer specimens were from the same individual patients (166). Similarly, HPV-associated cervical infections can precede the development of same type HPV-positive breast cancer in the same patient (169). In a recent study based on the Taiwan National Health Insurance data base, it was shown that women with viral warts were at a 23% higher risk of developing breast cancer when compared with women not diagnosed with viral warts (170). The viral warts were assumed to be associated with HPVs. These observations confirm that HPV infections may precede the development of HPV-positive breast cancer.TransformationHuman papilloma viruses immortalize and transform human mammary epithelial cells (171). HPV type 16 E6 and E7 oncoproteins convert non-invasive and non-metastatic breast cancer cells to invasive and metastatic phenotypes (172).TransmissionHuman papilloma virus-positive breast cancer is more common in young when compared with older women, an observation which is compatible with sexual transmission of HPVs among sexually active younger women (173). HPVs have been identified in peripheral blood which is a possible means by which they are transferred from infected genitals to the breast (174).Oncogenic MechanismsThe prevalence of breast cancer is not increased in immunocompromised patients with AIDS or organ transplants (175). This is in contrast to the fivefold increase in HPV-associated cervical cancer in these patients (175). The implication is that any oncogenic influences of HPVs in breast cancer are indirect or there is a “hit and run” viral influence where the virus initiates cancer or plays a role in cancer development, but then disappears from tumor cells (probably by immune surveillance) by the time the cancer is clinically detected (176). HPVs appear to influence the cell cycle control enzyme APOBEC which leads to genomic instability and ultimately to breast cancer (93, 94). There is high HPV E7 oncoprotein expression in benign breast tissues and low HPV E7 expression in subsequent breast cancer which developed in the same patients (176). These observations are compatible with the viral “hit and run” hypothesis.Human papilloma viruses may collaborate with other oncogenic viruses such as EBV and MMTV to cause breast cancer. The evidence for collaboration between HPVs and EBVs is limited and mainly consists as an association (22, 177, 178). There is preliminary experimental evidence which supports this notion (179). The influence of HPVs on MMTV and human breast cancer has been discussed in detail under the previous section on MMTV and breast cancer.Epstein–Barr VirusIdentification of EBV in Human Breast TissuesEpstein–Barr viruses are the cause of lymphomas and may be associated with additional cancers. Various EBV genes have been identified in breast cancer in a wide range of countries by in situ hybridization, immunohistochemistry, in situ PCR and by standard liquid PCR (Table (Table6).6). The details of these studies are based on a meta-analysis by Richardson et al. (180). Only case control studies with adequate controls are included in Table Table6.6. Many studies of EBVs in breast cancer based on PCR are not valid because standard PCR techniques cannot distinguish between cancer cells and infiltrating lymphocytes. Such studies have not been included in Table Table6.6. All listed studies used methods which identified EBV in breast cancer cells and included non-cancer breast tissue controls. Studies with negative outcomes conducted in locations where other studies had positive outcomes were excluded.Table 6Epstein–Barr virus (EBV) identification in breast cancer (case control studies).ReferenceLocationIdentification techniqueBreast cancerNon cancer breast controlLabrecque et al. (154)United KingdomPCR; ISH12/19 (63%)0/17 (0%)Bonnet et al. (155)FrancePCR; IHC;ISH51/100 (51%)0/30 (0%)Grinstein et al. (156)USPCR; IHC14/33 (42%)0/21 (0%)Preciado et al. (157)ArgentinaPCR; IHC24/39 (35%)0/17 (0%)Fawzy et al. (158)EgyptPCR; IHC10/40 (25%)0/20 (0%)Joshi et al. (159)IndiaIHC28/51 (55%)0/30 (0%)Lorenzetti et al. (160)ArgentinaIHC, ISH,PCR22/71 (31%)0/48 (0%)Zekri et al. (161)Egypt/IraqPCR; ISH32/90 (36%)0/20 (0%)Glenn et al. (22)AustraliaIS PCRPCR5/27 (19%)6/18 (33%)Yahia et al. (162)SudanPCR; ISH18/18 (100%)0/50 (0%)El-Naby et al. (163)EgyptPCR; IHC10/42 (24%)6/42 (14%)Pai et al. (164)IndiaISH25/83 (30%)0/7 (0%)Open in a separate windowThere is a consistent identification of EBV in breast cancers when compared with mostly negative controls.PCR, polymerase chain reaction; IHC, immunohistochemistry; ISH, in situ hybridization.The positive identification of EBV in breast cancer varies from 24 to 100% (Table (Table6).6). EBV was identified in non-cancer breast controls in only 2 of 13 studies (Table (Table66).Epstein–Barr virus has been identified in over 97% of breast cancer patients and 98% of normal controls by serological methods in two independent studies conducted on Australian and Norwegian subjects (181). In a study conducted in south China, EBV antibody levels were significantly higher in breast cancer patients when compared with controls with an odds ratio of 1.7 (182).EpidemiologyEpstein–Barr virus is accepted as a major contributor to Hodgkin lymphoma and there are significant correlations between the incidence of both Hodgkin lymphoma and breast cancer which suggests that EBV may also contribute to some breast cancers (183). In a recent study of all subtypes of EBV in peripheral blood mononuclear cells, overall, no differences were identified between patients with breast cancer and controls (184). However, EBV subtype D was associated with an increased breast cancer risk—OR 2.86 (184).TemporalityEpstein–Barr virus gene sequences have been identified in benign breast tissues prior to the development of EBV-positive breast cancer (185). The prior benign and later breast cancer specimens were from the same individual patients (185).TransmissionEpstein–Barr virus is mostly transmitted from person to person via saliva. Infection is almost universal but occurs later among Western when compared with economically developing communities. Breast epithelial cells can be infected with EBV by cell to cell contact (186).Oncogenic MechanismsEpstein–Barr virus infection predisposes breast epithelial cells to malignant transformation through activation of HER2/HER3 signaling cascades (187). HER2 and HER3 are two of the cellular oncogenes known to be involved in human breast cancer development and associated with a relatively poor prognosis.Multiple Viruses in Breast CancerEpstein–Barr virus and HPV gene sequences are colocated in 32% of breast cancers can be colocated in the same women (22). Glenn et al. have demonstrated that MMTV, HPV, and EBV gene sequences are present in over 50% of Australian breast cancers and in over 20% of epithelial cells in breast milk from normal lactating women (22). In this same study, MMTV, HPV, and EBV were shown by in situ PCR to be located in the same breast cancer cells (22). Corbex et al. have identified EBV and HPVs in the same inflammatory breast cancers among Algerian women (174). Naushad et al. have identified EBV, high-risk HPV, and MMTV in the same breast cancers among Pakistan women (34).The presence of EBV alongside HPV16 in cervical smears has been shown to correlate with a five to sevenfold increased likelihood of HPV integration into the host genome, suggesting that the presence of EBV may enhance genomic instability of HPV-infected cervical epithelial cells (188). EBV may also play an indirect role by interfering with the immune response to HPV-transformed cells through the production of the viral BCRF1 gene product, an interleukin-10 homolog (189). These observations provide evidence that these viruses can both collaborate to increase their oncogenic potential.In a recent report, it has been shown that MMTV, high-risk HPVs, BLV, and EBVs may be present in normal or benign breast tissues 1–11 years before the development of breast cancer in which the same viruses have been identified (185). The prior benign and later breast cancer specimens were from the same individual patients (185). These studies were based on the same normal breast (from cosmetic surgery), benign breast and breast cancer tissues from Australian women. The investigations were conducted in laboratories in Pisa and New York (MMTV), Berkeley (BLV), and Sydney (HPV and EBV) (22, 37, 115, 166). MMTV was identified in 3 (18%) of 17 normal controls, 6 (24%) of 25 benign breast specimens and 9 (36%) of 25 breast cancer specimens. BLV was identified in 6 (35%) of 17 normal controls, 18 (78%) of 23 benign breast specimens, and 20 (91%) of 22 breast cancer specimens. High-risk HPVs were identified in 13 (72%) of 17 normal controls, 13 (76%) of 17 benign breast specimens, and 13 (76%) of 17 breast cancer specimens. EBV was not identified in any benign breast specimens but was identified in 3 (25%) of 12 breast cancer specimens. These are important observations as the presence of viruses in breast and other tissues, prior to the development of cancer, is an essential causal criterion (1).DiscussionOur overall aim in this review has been to evaluate the evidence in studies which employed different techniques rather than relying on one technique such as PCR. PCR based data often receives much criticism mainly because of the well recognized problems of contamination leading to false positive outcomes. This is the reason for our consideration of a range of investigative techniques and why we have been careful about which PCR data is reported in this review. We have concluded that the prevalence of MMTV, BLV, HPV, and EBV is significantly higher in breast cancer tissues when compared with normal or benign control breast tissues. The presence of these infectious agents in normal or benign tissues before the development of cancer is a key criteria for a causal role in cancer (1). MMTV, BLV, HPV, and EBV are present in normal or benign breast tissues prior to the development of the same virus invasive breast cancers in the same patients (185). In our view, each of these oncoviruses has a potential role in human breast cancer.Mouse Mammary Tumor VirusWith respect to MMTV and human breast cancer, the evidence is detailed and comprehensive and meets all the causal criteria except for doubts about the possible absence of an immune response. The parallels in the evidence between MMTV caused mouse mammary tumors and MMTV-like associated human breast cancer, are almost identical with the exception of the likely means of transmission. However, the underlying mechanisms for any oncogenic influences of MMTV in human breast cancer are far from clear. It is likely that any such mechanisms differ in human breast cancer from mouse mammary tumors. Despite this lack of information, it is likely that MMTV-like viruses have a similar oncogenic role in human breast cancer to MMTV in rodent mammary tumors.However, several authors including Goedert et al., Joshi and Buehring, and Perzova et al. (4, 59, 190) have argued against a role of MMTV in human breast cancer. Goedert et al. did not identify MMTV antibodies in serum from women with proven breast cancer and therefore suggested that MMTV did not have a role in breast cancer (59). The reason for this negative finding is not clear and is in contrast to studies in which MMTV linked antibodies were repeatedly identified (56, 57). Joshi and Buehring have criticized the techniques used in several studies and have suggested the results are not reliable (4). Holland and Pogo have refuted the views of Joshi and Buehring by the presentation of published evidence (191). In our view, this evidence presented by Holland and Pogo is sound. Perzova et al. have recently suggested that the results of many studies of MMTV in breast cancer are contaminated by rodent MMTV gene sequences or by laboratory contamination (190). While such contamination may have occurred in some studies, it is unlikely to have occurred in the many independent laboratories in many countries where these studies have been conducted. In addition, it has been demonstrated in a recent study that there were no rodent MMTV sequences in any human breast cancer specimens (37). Tang and Larsson have recently reviewed studies of oncogenic viruses in a range of human cancers based on whole-genome sequencing (also known as Next Generation Sequencing or massive parallel sequencing) (192). They confirm the identification of MMTV in breast cancer but cannot exclude contamination (192, 193).Although premature at this stage of research, it is of interest that the development of preventive and therapeutic vaccines against MMTV in humans is a practical proposition. MMTV-associated mouse mammary tumors can be prevented from developing by immunization with purified mammary tumor virus (194–196). MMTV virus envelope peptides have also been used to prevent MMTV-associated mouse breast cancers (197). The effectiveness of these vaccines is convincing evidence that MMTV is causal in MMTV-associated mouse mammary tumors. Recently, the Hochman group working in Israel, together with the Bevilacqua group in Italy, have identified the MMTV envelope protein as a target for both prevention and treatment of MMTV-associated breast and other cancers (198).Bovine Leukemia VirusThe possibility that BLV may have a role in human breast cancer is of great importance because of the almost universal life long consumption of beef, cow’s milk and dairy products in all Western countries and to an increasing extent in Asian countries such as Japan and China. Almost all of the evidence for such a role has been produced by Buehring et al. at The University of California at Berkeley. There is an urgent need for their work to be replicated and expanded by others.In view of the emerging information about BLV in human breast cancer, veterinary authorities currently believe it is prudent to encourage BLV eradication programs in the dairy industry on a global basis (199).Human Papilloma VirusesThe evidence for a role of HPVs in breast cancer is substantial but not conclusive. Because the prevalence of breast cancer is not increased in immunocompromised patients with AIDS or organ transplants any oncogenic influences of HPVs in breast cancer are probably indirect. There may be a “hit and run” viral influence where the virus initiates cancer or plays a role in cancer development, but then disappears from tumor cells (probably by immune surveillance) by the time the cancer is clinically detected (176). HPVs also appear to influence the cell cycle control enzyme APOBEC which leads to genomic instability and ultimately to breast cancer (93, 94).Human papilloma viruses may collaborate with other oncogenic viruses such as EBV and MMTV to cause breast cancer. The evidence for collaboration between HPVs and EBVs is limited and mainly consists as an association (22, 177, 178). There is preliminary experimental evidence which supports this notion (179). The indirect influence of HPVs on MMTV and human breast cancer has been discussed in detail under the previous section on MMTV and breast cancer.In a recent review, Tang and Larsson state “Frequent clonal presence and expression of EBV and HPV (in breast cancers) can be ruled out, considering that transcriptomic data from more than 800 breast tumors have now been analyzed without any significant levels of these viruses being detected.” These conclusions are based on whole-genome sequencing studies published in 2013 (43). Since that time a study, using whole-genome sequencing and also based on the same TCGA series of over 800 breast tumors as the Tang et al. study, has confirmed the presence of high-risk HPVs (166). These differences in results may be because HPVs in breast cancer do not appear to express transcripts which potentially produce oncogenic proteins (193). It is possible that HPVs have an indirect oncogenic influence on breast cancer via their influence on APOBEC enzymes (93, 94).Epstein–Barr VirusThe higher prevalence of EBV in breast cancer when compared with controls is consistent. Although EBV gene sequences have been identified in benign breast tissues prior to the development of EBV-positive breast cancer, the importance of this observation is lessened because of the ubiquitous presence of EBV. Of more importance is the recognition that EBV infection predisposes breast epithelial cells to malignant transformation through activation of HER2/HER3 signaling cascades (189). The apparent collaboration between EBV and HPVs is of considerable interest but requires additional investigation (22, 177, 178). This evidence is substantial but not conclusive.Several of these four oncoviruses are colocated in breast cancer cells and may collaborate with each other to increase their oncogenic potential. HPVs and EBV can be colocated in breast cancer cells (22). MMTV gene sequences may also be collocated with HPVs and EBVs in the same breast cancer cells (22). Because the prevalence of BLV is high in both benign breast and later breast cancer cells (78% of benign breast and 91% of breast cancer specimens), it is likely that this virus is also colocated with other virus positive benign and breast cancer cells (115). However, there is no direct evidence of such colocation. Nor is there evidence that such colocation of these viruses leads to increased oncogenic influences in breast cancer. On the other hand, in studies of women with breast cancer in Syria, it was shown that a coprevalence of EBVs and high-risk HPVs in 32% of the breast tumors was associated with high grade invasive ductal breast cancers (178). In addition there is preliminary experimental evidence that HPVs and EBVs collaborate (179). It is not known how different viruses cooperate to induce cancer.It is possible that different viruses are associated with different types of breast cancer. For example MMTV positive human breast cancers frequently have the same histological characteristics as MMTV positive mouse mammary tumors (30, 78). These tumors are very similar to many breast ductal carcinoma in situ breast cancers and special breast cancer types such as medullary carcinoma, adenoid cystic carcinoma and neuro-endocrine carcinoma (78, 200, 201). In addition putative koilocytes have been observed in HPV-associated breast cancers (167).It is important to note that the prevalence of breast cancer is not increased in immunocompromised patients with AIDS or organ transplants (175). This is in contrast to the fivefold increase in HPV-associated cervical cancer in these patients (175). The implication is that any oncogenic influences of these viruses in breast cancer are indirect or there is a “hit and run” viral influence. There is evidence in support of both notions. HPVs appear to influence the cell cycle control enzyme APOBEC which leads to genomic instability and ultimately to breast cancer (93). There is high HPV E7 oncoprotein expression in benign breast tissues and low HPV E7 expression in subsequent breast cancer which developed in the same patients (176).Alternative Breast Cancer Causal HypothesesIn addition to the viral causal hypothesis for breast cancer, there are two other main hypotheses. These are (1) a genetic cause and (2) aberrant stem cells. These three hypotheses are not necessarily mutually exclusive as viruses, genetics, and stem cells could conceivably each contribute to breast cancer. It also likely that subsets breast cancers arise due to different initiation events. Thus it is unlikely there is only one cause of breast cancers and more likely it arises as a consequence of a number of events occurring.GeneticsDuring the past two decades, there has been an intense research effort directed at finding a genetic cause of breast cancer. It is clear that there is a strong genetically based susceptibility to develop breast cancer (202, 203). This disposition appears in many cases to be familial (204). The classical example is inheritance of the BRCA 1 and 2 genes. However, there is no apparent evidence that normal or mutated genes are the initial cause of breast cancer.Aberrant Stem CellsThe cancer stem cell theory postulates that tumors carry a subpopulation of cells that share properties of stem cells including the ability to self-renew and show indefinite replicative potential as well as initiate tumor formation, indefinite replicative potential. However, despite intense research efforts there is no apparent evidence that normal or aberrant stem cells are the initial cause of breast cancer (205, 206).ConclusionThe influence of oncogenic viruses is currently the major plausible hypothesis for a direct cause of human breast cancer. Genetic studies have demonstrated that there are variations in the susceptibility to develop breast cancer of which the BRCA 1 and 2 genes are the most notorious. However, although there is evidence of genetic predisposition, and cancer in general is a culmination of events, there is no evidence that inherited genetic traits are causal.Mouse mammary tumor virus and human breast cancer—the evidence is detailed and comprehensive but cannot be regarded as conclusive.Bovine leukemia virus and human breast cancer—the evidence is limited. However, in view of the emerging information about BLV in human breast cancer, it is prudent to encourage a BLV eradication program in the dairy industry. This has been successfully achieved by voluntary approaches in Australia and several European countries.Human papilloma viruses and breast cancer—the evidence is substantial but not conclusive. The availability of effective preventive vaccines is a major advantage and their use should be encouraged.Epstein–Barr virus and breast cancer—the evidence is also substantial but not conclusive. Currently, there are no practical means of either prevention or treatment.Author ContributionsJL, BS, and WG added to the concepts, reviewed the literature, and participated in the preparation of the manuscript.Conflict of Interest StatementThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.AcknowledgmentsJack Hirsh of McMaster University, Canada and Walter H Gunzburg of the University Veterinary Medicine, Vienna, Austria gave valuable advice.AbbreviationsMMTV, mouse mammary tumor virus; BLV, bovine leukemia virus; HPV, human papilloma virus; EBV, Epstein–Barr virus; PCR, polymerase chain reaction; LTR, long terminal repeat; gag, group specific antigen; pol, polymerase; env, envelope; TCGA, the cancer genome atlas; GP, glycoprotein.References1. Hill AB.
The environment and disease: association or causation?
Proc R Soc Med (1965) 58:295–330. [PMC free article] [PubMed] [Google Scholar]2. Vinner L, Mourier T, Friis-Nielsen J, Gniadecki R, Dybkaer K, Rosenberg J, et al.
Investigation of human cancers for retrovirus by low-stringency target enrichment and high-throughput sequencing. Sci Rep (2015) 5:13201. 10.1038/srep13201 [PMC free article] [PubMed] [CrossRef] [Google Scholar]3. Khan NA, Castillo A, Koriyama C, Kijima Y, Umekita Y, Ohi Y, et al.
Human papillomavirus detected in female breast carcinomas in Japan. Br J Cancer (2008) 99:408–14. 10.1038/sj.bjc.6604502 [PMC free article] [PubMed] [CrossRef] [Google Scholar]4. Joshi D, Buehring GC. Are viruses associated with human breast cancer? Scrutinizing the molecular evidence. Breast Cancer Res Treat (2012) 135(1):1–15. 10.1007/s10549-011-1921-4 [PubMed] [CrossRef] [Google Scholar]5. Bittner JJ.
Some possible effects of nursing on the mammary gland tumor incidence in mice. Science (1936) 84(2172):162. 10.1126/science.84.2172.162 [PubMed] [CrossRef] [Google Scholar]6. Graff S, Moore DH, Stanley WM, Randall HT, Haagensen CD.
Isolation of mouse mammary carcinoma virus. Cancer (1949) 2:755–62. 10.1002/1097-0142(194909)2:5<755::AID-CNCR2820020503>3.0.CO;2-4 [PubMed] [CrossRef] [Google Scholar]7. Duesberg PH, Blair PB.
Isolation of the nucleic acid of mouse mammary tumor virus (MMTV). Proc Natl Acad Sci U S A (1966) 55:1490–7. 10.1073/pnas.55.6.1490 [PMC free article] [PubMed] [CrossRef] [Google Scholar]8. Dudley JP, Golovkina TV, Ross SR. Lessons learned from mouse mammary tumor virus in animal models. ILAR J (2016) 57:12–23. 10.1093/ilar/ilv044 [PMC free article] [PubMed] [CrossRef] [Google Scholar]9. Szabo S, Haislip AM, Traina-Dorge V, Costin JM, Crawford BE, II, Wilson RB, et al.
Microsc human, rhesus macaque, and feline sequences highly similar to mouse mammary tumor virus sequences. Microsc Res Tech (2005) 68(3–4):209–21. 10.1002/jemt.20233 [PubMed] [CrossRef] [Google Scholar]10. Axel R, Schlom J, Spiegelman S.
Presence in human breast cancer of RNA homologous to mouse mammary tumour virus RNA. Nature (1972) 235:32–6. 10.1038/235032a0 [PubMed] [CrossRef] [Google Scholar]11. Crépin M, Lidereau R, Chermann JC, Pouillart P, Magdamenat H, Montagnier L.
Sequences related to mouse mammary tumor virus genome in tumor cells and lymphocytes from patients with breast cancer. Biochem Biophys Res Commun (1984) 118:324–31. 10.1016/0006-291X(84)91104-5 [PubMed] [CrossRef] [Google Scholar]12. Franklin GC, Chretien S, Hanson IM, Rochefort H, May FE, Westley BR. Expression of human sequences related to those of mouse mammary tumor virus. J Virol (1988) 62:1203–10. [PMC free article] [PubMed] [Google Scholar]13. Szakacs JG, Moscinski LC. Sequence homology of deoxyribonucleic acid to mouse mammary tumor virus genome in human breast tumors. Ann Clin Lab Sci (1991) 21:402–12. [PubMed] [Google Scholar]14. Salmons B, Lawson JS, Günzburg WH. Recent developments linking retroviruses to human breast cancer: infectious agent, enemy within or both?
J Gen Virol (2014) 95(Pt 12):2589–93. 10.1099/vir.0.070631-0 [PubMed] [CrossRef] [Google Scholar]15. Wang Y, Holland JF, Bleiweiss IJ, Melana S, Liu X, Pelisson I, et al.
Detection of mammary tumor virus env gene-like sequences in human breast cancer. Cancer Res (1995) 55:5173–9. [PubMed] [Google Scholar]16. Callahan R, Drohan W, Tronick S, Schlom J. Detection and cloning of human DNA sequences related to the mouse mammary tumor virus genome. Proc Natl Acad Sci U S A (1982) 79:5503–7. 10.1073/pnas.79.18.5503 [PMC free article] [PubMed] [CrossRef] [Google Scholar]17. May FE, Westley BR, Rochefort H, Buetti E, Diggelmann H. Mouse mammary tumour virus related sequences are present in human DNA. Nucleic Acids Res (1983) 11:4127–39. 10.1093/nar/11.12.4127 [PMC free article] [PubMed] [CrossRef] [Google Scholar]18. Westley B, May FE. The human genome contains multiple sequences of varying homology to mouse mammary tumour virus DNA. Gene (1984) 28:221–7. 10.1016/0378-1119(84)90259-2 [PubMed] [CrossRef] [Google Scholar]19. Wang F, Hou J, Shen Q, Yue Y, Xie F, Wang X, et al.
Mouse mammary tumor virus-like virus infection and the risk of human breast cancer: a meta-analysis. Am J Transl Res (2014) 6:248–66. [PMC free article] [PubMed] [Google Scholar]20. Ford CE, Faedo M, Rawlinson WD. Mouse mammary tumor virus-like RNA transcripts and DNA are found in affected cells of human breast cancer. Clin Cancer Res (2004) 10:7284–9. 10.1158/1078-0432.CCR-04-0767 [PubMed] [CrossRef] [Google Scholar]21. Mazzanti CM, Al Hamad M, Fanelli G, Scatena C, Zammarchi F, Zavaglia K, et al.
A mouse mammary tumor virus env-like exogenous sequence is strictly related to progression of human sporadic breast carcinoma. Am J Pathol (2011) 179:2083–90. 10.1016/j.ajpath.2011.06.046 [PMC free article] [PubMed] [CrossRef] [Google Scholar]22. Glenn WK, Heng B, Delprado W, Iacopetta B, Whitaker NJ, Lawson JS.
Epstein-Barr virus, human papillomavirus and mouse mammary tumour virus as multiple viruses in breast cancer. PLoS One (2012) 7:e48788. 10.1371/journal.pone.0048788 [PMC free article] [PubMed] [CrossRef] [Google Scholar]23. Etkind P, Du J, Khan A, Pillitteri J, Wiernik PH. Mouse mammary tumor virus-like env gene sequences in human breast tumors and in a lymphoma of a breast cancer patient. Clin Cancer Res (2000) 6:1273–8. [PubMed] [Google Scholar]24. Melana SM, Holland JF, Pogo BG. Search for mouse mammary tumor virus-like env sequences in cancer and normal breast from the same individuals. Clin Cancer Res (2001) 7:283–4. [PubMed] [Google Scholar]25. Melana SM, Picconi MA, Rossi C, Mural J, Alonio LV, Teyssié A, et al.
Detection of murine mammary tumor virus (MMTV) env gene-like sequences in breast cancer from Argentine patients. Medicina (B Aires) (2002) 62:323–7. [PubMed] [Google Scholar]26. Ford CE, Tran DD, Deng YM, Rawlinson WD, Lawson JS.
Mouse mammary tumour like virus prevalence in breast tumours of Australian and Vietnamese women. Clin Cancer Res (2003) 9:1118–20. [PubMed] [Google Scholar]27. Zammarchi F, Pistello M, Piersigilli A, Murr R, Di Cristofano C, Naccarato AG, et al.
MMTV-like sequences in human breast cancer: a fluorescent PCR/laser microdissection approach. J Pathol (2006) 209:436–44. 10.1002/path.1997 [PubMed] [CrossRef] [Google Scholar]28. Bindra A, Muradrasoli S, Kisekka R, Nordgren H, Wärnberg F, Blomberg J. Search for DNA of exogenous mouse mammary tumor virus-related virus in human breast cancer samples. J Gen Virol (2007) 88:1806–9. 10.1099/vir.0.82767-0 [PubMed] [CrossRef] [Google Scholar]29. Hachana M, Trimeche M, Ziadi S, Amara K, Gaddas N, Mokni M, et al.
Prevalence and characteristics of the MMTV-like associated breast carcinomas in Tunisia. Cancer Lett (2008) 271:222–30. 10.1016/j.canlet.2008.06.001 [PubMed] [CrossRef] [Google Scholar]30. Lawson JS, Glenn WK, Salmons B, Ye Y, Heng B, Moody P, et al.
Mouse mammary tumor virus-like sequences in human breast cancer. Cancer Res (2010) 70(9):3576–85. 10.1158/0008-5472.CAN-09-4160 [PubMed] [CrossRef] [Google Scholar]31. Slaoui M, El Mzibri M, Razine R, Qmichou Z, Attaleb M, Amrani M. Detection of MMTV-Like sequences in Moroccan breast cancer cases. Infect Agent Cancer (2014) 9:37. 10.1186/1750-9378-9-37 [PMC free article] [PubMed] [CrossRef] [Google Scholar]32. Cedro-Tanda A, Córdova-Solis A, Juárez-Cedillo T, Pina-Jiménez E, Hernández-Caballero ME, Moctezuma-Meza C, et al.
Prevalence of HMTV in breast carcinomas and unaffected tissue from Mexican women. BMC Cancer (2014) 14:942. 10.1186/1471-2407-14-942 [PMC free article] [PubMed] [CrossRef] [Google Scholar]33. Reza MA, Reza MH, Mahdiyeh L, Mehdi F, Hamid ZN. Evaluation frequency of Merkel Cell Polyoma, Epstein-Barr and mouse mammary tumor viruses in patients with breast cancer in Kerman, southeast of Iran. Asian Pac J Cancer Prev (2015) 16:7351–7. 10.7314/APJCP.2015.16.16.7351 [PubMed] [CrossRef] [Google Scholar]34. Naushad W, Surriya O, Sadia H. Prevalence of EBV, HPV and MMTV in Pakistani breast cancer patients: a possible etiological role of viruses in breast cancer. Infect Genet Evol (2017) 54:230–7. 10.1016/j.meegid.2017.07.010 [PubMed] [CrossRef] [Google Scholar]35. Shariatpanahi S, Farahani N, Salehi AR, Salehi R. High prevalence of mouse mammary tumor virus-like gene sequences in breast cancer samples of Iranian women. Nucleosides Nucleotides Nucleic Acids (2017) 36(10):621–30. 10.1080/15257770.2017.1360498 [PubMed] [CrossRef] [Google Scholar]36. Stewart THM, Sage RD, Stewart AFR, Cameron DW. Breast cancer incidence highest in the range of one species of house mouse, Mus domesticus. Br J Cancer (2000) 82:446–51. 10.1054/bjoc.1999.0941 [PMC free article] [PubMed] [CrossRef] [Google Scholar]37. Nartey T, Mazzanti CM, Melana S, Glenn WK, Bevilacqua G, Holland JF, et al.
Mouse mammary tumor-like virus (MMTV) is present in human breast tissue before development of virally associated breast cancer. Infect Agent Cancer (2017) 12:1. 10.1186/s13027-017-0126-9 [PMC free article] [PubMed] [CrossRef] [Google Scholar]38. Fukuoka H, Moriuchi M, Yano H, Nagayasu T, Moriuchi H. No association of mouse mammary tumor virus-related retrovirus with Japanese cases of breast cancer. J Med Virol (2008) 80:1447–51. 10.1002/jmv.21247 [PubMed] [CrossRef] [Google Scholar]39. Park DJ, Southey MC, Giles GG, Hopper JL. No evidence of MMTV-like env sequences in specimens from the Australian Breast Cancer Family Study. Breast Cancer Res Treat (2011) 125:229–35. 10.1007/s10549-010-0946-4 [PubMed] [CrossRef] [Google Scholar]40. Morales-Sánchez A, Molina-Muñoz T, Martínez-López JL, Hernández-Sancén P, Mantilla A, Leal YA, et al.
No association between Epstein-Barr virus and mouse mammary tumor virus with breast cancer in Mexican women. Sci Rep (2013) 3:2970. 10.1038/srep02970 [PMC free article] [PubMed] [CrossRef] [Google Scholar]41. Naushad W, Bin Rahat T, Gomez MK, Ashiq MT, Younas M, Sadia H. Detection and identification of mouse mammary tumor virus-like DNA sequences in blood and breast tissues of breast cancer patients. Tumour Biol (2014) 35:8077–86. 10.1007/s13277-014-1972-3 [PubMed] [CrossRef] [Google Scholar]42. Hizi A, Herzig E. dUTPase: the frequently overlooked enzyme encoded by many retroviruses. Retrovirology (2015) 12:70. 10.1186/s12977-015-0198-9 [PMC free article] [PubMed] [CrossRef] [Google Scholar]43. Tang KW, Alaei-Mahabadi B, Samuelsson T, Lindh M, Larsson E. The landscape of viral expression and host gene fusion and adaptation in human cancer. Nat Commun (2013) 4:2513. 10.1038/ncomms3513 [PMC free article] [PubMed] [CrossRef] [Google Scholar]44. Larsson Lab. (2013). Available from: http://larssonlab.org/tcga-viruses/report_BRCA.php45. Liu B, Wang Y, Melana SM, Pelisson I, Najfeld V, Holland JF, et al.
Identification of a proviral structure in human breast cancer. Cancer Res (2001) 61:1754–9. [PubMed] [Google Scholar]46. Melana SM, Nepomnaschy I, Sakalian M, Abbott A, Hasa J, Holland JF, et al.
Characterization of viral particles isolated from primary cultures of human breast cancer cells. Cancer Res (2007) 67:8960–5. 10.1158/0008-5472.CAN-06-3892 [PubMed] [CrossRef] [Google Scholar]47. Moore R, Dixon M, Smith R, Peters G, Dickson C. Complete nucleotide sequence of a milk-transmitted mouse mammary tumor virus: two frameshift suppression events are required for translation of gag and pol. J Virol (1987) 61:480–90. [PMC free article] [PubMed] [Google Scholar]48. Johal H, Faedo M, Faltas J, Lau A, Mousina R, Cozzi P, et al.
DNA of mouse mammary tumor virus-like virus is present in human tumors influenced by hormones. J Med Virol (2010) 82:1044–50. 10.1002/jmv.21754 [PubMed] [CrossRef] [Google Scholar]49. Deligdisch L, Marin T, Lee AT, Etkind P, Holland JF, Melana S, et al.
Human mammary tumor virus (HMTV) in endometrial carcinoma. Int J Gynecol Cancer (2013) 23:1423–8. 10.1097/IGC.0b013e3182980fc5 [PubMed] [CrossRef] [Google Scholar]50. Xu L, Sakalian M, Shen Z, Loss G, Neuberger J, Mason A. Cloning the human betaretrovirus proviral genome from patients with primary biliary cirrhosis. Hepatology (2004) 39:151–6. 10.1002/hep.20024 [PubMed] [CrossRef] [Google Scholar]51. Klein A, Wessel R, Graessmann M, Jürgens M, Petersen I, Schmutzler R, et al.
Comparison of gene expression data from human and mouse breast cancers: identification of a conserved breast tumor gene set. Int J Cancer (2007) 121:683–8. 10.1002/ijc.22630 [PubMed] [CrossRef] [Google Scholar]52. Callahan R, Mudunur U, Bargo S, Raafat A, McCurdy D, Boulanger C, et al.
Genes affected by mouse mammary tumor virus (MMTV) proviral insertions in mouse mammary tumors are deregulated or mutated in primary human mammary tumors. Oncotarget (2012) 3:1320–34. 10.18632/oncotarget.682 [PMC free article] [PubMed] [CrossRef] [Google Scholar]53. Melana SM, Nepomnaschy I, Hasa J, Djougarian A, Djougarian A, Holland JF, et al.
Detection of human mammary tumor virus proteins in human breast cancer cells. J Virol Methods (2010) 163:157–61. 10.1016/j.jviromet.2009.09.015 [PubMed] [CrossRef] [Google Scholar]54. Tomana M, Kajdos AH, Niedermeier W, Durkin WJ, Mestecky J. Antibodies to mouse mammary tumor virus-related antigen in sera of patients with breast carcinoma. Cancer (1981) 47:2696–703. 10.1002/1097-0142(19810601)47:11<2696::AID-CNCR2820471128>3.0.CO;2-7 [PubMed] [CrossRef] [Google Scholar]55. Mesa-Tejada R, Keydar I, Ramanarayanan M, Ohno T, Fenoglio C, Spiegelman S. Immunohistochemical evidence for RNA virus related components in human breast cancer. Ann Clin Lab Sci (1979) 9:202–11. [PubMed] [Google Scholar]56. Day NK, Witkin SS, Sarkar NH, Kinne D, Jussawalla DJ, Levin A, et al.
Antibodies reactive with murine mammary tumor virus in sera of patients with breast cancer: geographic and family studies. Proc Natl Acad Sci U S A (1981) 78:2483–7. 10.1073/pnas.78.4.2483 [PMC free article] [PubMed] [CrossRef] [Google Scholar]57. Lopez DM, Parks WP, Silverman MA, Distasio JA. Lymphoproliferative responses to mouse mammary tumor virus in lymphocyte subsets of breast cancer patients. J Natl Cancer Inst (1981) 67:353–8. [PubMed] [Google Scholar]58. Dion AS, Girardi AJ, Williams CC, Pomenti AA. Serologic responses to murine mammary tumor virus (MuMTV) in MuMTV-exposed laboratory personnel. J Natl Cancer Inst (1986) 76:611–9. 10.1093/jnci/76.4.611 [PubMed] [CrossRef] [Google Scholar]59. Goedert JJ, Rabkin CS, Ross SR. Prevalence of serologic reactivity against four strains of mouse mammary tumour virus among US women with breast cancer. Br J Cancer (2006) 94:548–51. 10.1038/sj.bjc.6602977 [PMC free article] [PubMed] [CrossRef] [Google Scholar]60. Wei WZ, Gill RF, Wang H.
Mouse mammary tumor virus associated antigens and superantigens – immuno-molecular correlates of neoplastic progression. Semin Cancer Biol (1993) 4:205–13. [PubMed] [Google Scholar]61. Wang Y, Jiang JD, Xu D, Li Y, Qu C, Holland JF, et al.
A mouse mammary tumor virus-like long terminal repeat superantigen in human breast cancer. Cancer Res (2004) 64:4105–11. 10.1158/0008-5472.CAN-03-3880 [PubMed] [CrossRef] [Google Scholar]62. Labrecque N, McGrath H, Subramanyam M, Huber BT, Sékaly RP. Human T cells respond to mouse mammary tumor virus-encoded superantigen: V beta restriction and conserved evolutionary features. J Exp Med (1993) 177:1735–43. 10.1084/jem.177.6.1735 [PMC free article] [PubMed] [CrossRef] [Google Scholar]63. Svec J, Hlavay E, Matoska J, Thurzo V. Hormone-responsive genes of the mouse mammary tumor virus. Czech Med (1979) 2:198–212. [PubMed] [Google Scholar]64. Briand P.
Hormone-dependent mammary tumors in mice and rats as a model for human breast cancer. Anticancer Res (1983) 3:273–81. [PubMed] [Google Scholar]65. McGrath CM, Jones RF. Hormonal induction of mammary tumor viruses and its implications for carcinogenesis. Cancer Res (1978) 38(11 Pt 2):4112–25. [PubMed] [Google Scholar]66. Wang Y, Melana SM, Baker B, Bleiweiss I, Fernandez-Cobo M, Mandeli JF, et al.
High prevalence of MMTV-like env gene sequences in gestational breast cancer. Med Oncol (2003) 20:233–6. 10.1385/MO:20:3:233 [PubMed] [CrossRef] [Google Scholar]67. Indik S, Günzburg WH, Kulich P, Salmons B, Rouault F. Rapid spread of mouse mammary tumor virus in cultured human breast cells. Retrovirology (2007) 4:73. 10.1186/1742-4690-4-73 [PMC free article] [PubMed] [CrossRef] [Google Scholar]68. Indik S, Günzburg WH, Salmons B, Rouault F. Mouse mammary tumor virus infects human cells. Cancer Res (2005) 65:6651–9. 10.1158/0008-5472.CAN-04-2609 [PubMed] [CrossRef] [Google Scholar]69. Konstantoulas CJ, Indik S. C3H strain of mouse mammary tumour virus, like GR strain, infects human mammary epithelial cells, albeit less efficiently than murine mammary epithelial cells. J Gen Virol (2015) 96(Pt 3):650–62. 10.1099/jgv.0.000006 [PubMed] [CrossRef] [Google Scholar]70. Faschinger A, Rouault F, Sollner J, Lukas A, Salmons B, Günzburg WH, et al.
Mouse mammary tumor virus integration site selection in human and mouse genomes. J Virol (2008) 82(3):13. 10.1128/JVI.02098-07 [PMC free article] [PubMed] [CrossRef] [Google Scholar]71. Etkind PR, Stewart AF, Wiernik PH. Mouse mammary tumor virus (MMTV)-like DNA sequences in the breast tumors of father, mother, and daughter. Infect Agent Cancer (2008) 3:2. 10.1186/1750-9378-3-2 [PMC free article] [PubMed] [CrossRef] [Google Scholar]72. Johal H, Ford C, Glenn W, Heads J, Lawson J, Rawlinson W. Mouse mammary tumor like virus sequences in breast milk from healthy lactating women. Breast Cancer Res Treat (2011) 129:149–55. 10.1007/s10549-011-1421-6 [PubMed] [CrossRef] [Google Scholar]73. Nartey T, Moran H, Marin T, Arcaro KF, Anderton DL, Etkind P, et al.
Human mammary tumor virus (HMTV) sequences in human milk. Infect Agent Cancer (2014) 9:20. 10.1186/1750-9378-9-20 [PMC free article] [PubMed] [CrossRef] [Google Scholar]74. Mazzanti CM, Lessi F, Armogida I, Zavaglia K, Franceschi S, Al Hamad M, et al.
Human saliva as route of inter-human infection for mouse mammary tumor virus. Oncotarget (2015) 6:18355–63. 10.18632/oncotarget.4567 [PMC free article] [PubMed] [CrossRef] [Google Scholar]75. Hsu WL, Lin HY, Chiou SS, Chang CC, Wang SP, Lin KH, et al.
Mouse mammary tumor virus-like nucleotide sequences in canine and feline mammary tumors. J Clin Microbiol (2010) 48:4354–62. 10.1128/JCM.01157-10 [PMC free article] [PubMed] [CrossRef] [Google Scholar]76. Laumbacher B, Fellerhoff B, Herzberger B, Wank R. Do dogs harbour risk factors for human breast cancer?
Med Hypotheses (2006) 67:21–6. 10.1016/j.mehy.2006.01.016 [PubMed] [CrossRef] [Google Scholar]77. Nguyen F, Peña L, Ibisch C, Loussouarn D, Gama A, Rieder N, et al.
Canine invasive mammary carcinomas as models of human breast cancer. Part 1: natural history and prognostic factors. Breast Cancer Res Treat (2017). 10.1007/s10549-017-4548-2 [PMC free article] [PubMed] [CrossRef] [Google Scholar]78. Lawson JS, Tran DD, Carpenter E, Ford CE, Rawlinson WD, Whitaker NJ, et al.
Presence of mouse mammary tumour-like virus gene sequences may be associated with specific human breast cancer morphology. J Clin Pathol (2006) 59:1287–92. 10.1136/jcp.2005.035907 [PMC free article] [PubMed] [CrossRef] [Google Scholar]79. Dunn T.
Morphology of mammary tumors in mice. In: Homburger F, editor. Physiopathology of Cancer. New York: A. J. Phiebig; (1959). p. 38–83. [Google Scholar]80. Wellings SR.
A hypothesis of the origin of human breast cancer from the terminal ductal lobular unit. Pathol Res Pract (1980) 166:515–35. 10.1016/S0344-0338(80)80248-2 [PubMed] [CrossRef] [Google Scholar]81. Hamilton JM.
Comparative aspects of mammary tumors. Adv Cancer Res (1974) 19:1–45. 10.1016/S0065-230X(08)60051-2 [PubMed] [CrossRef] [Google Scholar]82. Katz E, Lareef MH, Rassa JC, Grande SM, King LB, Russo J, et al.
MMTV env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture. J Exp Med (2005) 201:431–9. 10.1084/jem.20041471 [PMC free article] [PubMed] [CrossRef] [Google Scholar]83. Nusse R, Varmus HE.
Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell (1982) 31:99–109. [PubMed] [Google Scholar]84. Gattelli A, Zimberlin MN, Meiss RP, Castilla LH, Kordon EC. Selection of early-occurring mutations dictates hormone-independent progression in mouse mammary tumor lines. J Virol (2006) 80:11409–15. 10.1128/JVI.00234-06 [PMC free article] [PubMed] [CrossRef] [Google Scholar]85. Ross SR, Schmidt JW, Katz E, Cappelli L, Hultine S, Gimotty P, et al.
An immunoreceptor tyrosine activation motif in the mouse mammary tumor virus envelope protein plays a role in virus-induced mammary tumors. J Virol (2006) 80:9000–8. 10.1128/JVI.00788-06 [PMC free article] [PubMed] [CrossRef] [Google Scholar]86. Feldman D, Roniger M, Bar-Sinai A, Braitbard O, Natan C, Love DC, et al.
The signal peptide of mouse mammary tumor virus-env: a phosphoprotein tumor modulator. Mol Cancer Res (2012) 10:1077–86. 10.1158/1541-7786.MCR-11-0581 [PubMed] [CrossRef] [Google Scholar]87. Salmons B, Gunzburg WH.
Tumorigenesis mechanisms of a putative human breast cancer retrovirus. Austin Virol Retrovirol (2015) 2(1):1010. [Google Scholar]88. Monot M, Erny A, Gineys B, Desloire S, Dolmazon C, Aublin-Gex A, et al.
Early steps of Jaagsiekte sheep retrovirus-mediated cell transformation involve the interaction between env and the RALBP1 cellular protein. J Virol (2015) 89:8462–73. 10.1128/JVI.00590-15 [PMC free article] [PubMed] [CrossRef] [Google Scholar]89. Kincaid RP, Panicker NG, Lozano MM, Sullivan CS, Dudley JP, Mustafa F.
MMTV does not encode viral microRNAs but alters the levels of cancer-associated host microRNAs. Virology (2017) 513:180–7. 10.1016/j.virol.2017.09.030 [PMC free article] [PubMed] [CrossRef] [Google Scholar]90. Okeoma CM, Lovsin N, Peterlin BM, Ross SR. APOBEC3 inhibits mouse mammary tumour virus replication in vivo. Nature (2007) 445:927–30. 10.1038/nature05540 [PubMed] [CrossRef] [Google Scholar]91. Okeoma CM, Huegel AL, Lingappa J, Feldman MD, Ross SR. APOBEC3 proteins expressed in mammary epithelial cells are packaged into retroviruses and can restrict transmission of milk-borne virions. Cell Host Microbe (2010) 8:534–43. 10.1016/j.chom.2010.11.003 [PMC free article] [PubMed] [CrossRef] [Google Scholar]92. MacMillan AL, Kohli RM, Ross SR. APOBEC3 inhibition of mouse mammary tumor virus infection: the role of cytidine deamination versus inhibition of reverse transcription. J Virol (2013) 87:4808–17. 10.1128/JVI.00112-13 [PMC free article] [PubMed] [CrossRef] [Google Scholar]93. Ohba K, Ichiyama K, Yajima M, Gemma N, Nikaido M, Wu Q, et al.
In vivo and in vitro studies suggest a possible involvement of HPV infection in the early stage of breast carcinogenesis via APOBEC3B induction. PLoS One (2014) 9:e97787. 10.1371/journal.pone.0097787 [PMC free article] [PubMed] [CrossRef] [Google Scholar]94. Vieira VC, Leonard B, White EA, Starrett GJ, Temiz NA, Lorenz LD, et al.
Human papillomavirus E6 triggers upregulation of the antiviral and cancer genomic DNA deaminase APOBEC3B. MBio (2014) 5:e2234–2214. 10.1128/mBio.02234-14 [PMC free article] [PubMed] [CrossRef] [Google Scholar]95. Roberts SA, Lawrence MS, Klimczak LJ, Grimm SA, Fargo D, Stojanov P, et al.
An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat Genet (2013) 45:970–6. 10.1038/ng.2702 [PMC free article] [PubMed] [CrossRef] [Google Scholar]96. Nik-Zainal S, Wedge DC, Alexandrov LB, Petljak M, Butler AP, Bolli N, et al.
Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC dependent mutations in breast cancer. Nat Genet (2014) 46:487–91. 10.1038/ng.2955 [PMC free article] [PubMed] [CrossRef] [Google Scholar]97. Burns MB, Lackey L, Carpenter MA, Rathore A, Land AM, Leonard B, et al.
APOBEC3B is an enzymatic source of mutation in breast cancer. Nature (2013) 494:366–70. 10.1038/nature11881 [PMC free article] [PubMed] [CrossRef] [Google Scholar]98. Lefebvre C, Bachelot T, Filleron T, Pedrero M, Campone M, Soria JC, et al.
Mutational profile of metastatic breast cancers: a retrospective analysis. PLoS Med (2016) 13:e1002201. 10.1371/journal.pmed.1002201 [PMC free article] [PubMed] [CrossRef] [Google Scholar]99. Moore DH, Charney J, Kramarsky B, Lasfargues EY, Sarkar NH, Brennan MJ, et al.
Search for a human breast cancer virus. Nature (1971) 229:611–4. 10.1038/229611a0 [PubMed] [CrossRef] [Google Scholar]100. Feller WF, Chopra HC.
A small virus-like particle observed in human breast cancer by means of electron microscopy. J Natl Cancer Inst (1968) 40:1359–73. [PubMed] [Google Scholar]101. Nishio M, Xu L, Sasaki M, Haga S, Okumoto M, Mori N, et al.
Complete nucleotide sequence of mouse mammary tumor virus from JYG Chinese wild mice: absence of bacterial insertion sequences in the cloned viral gag gene. Breast Cancer (1994) 1:89–94. 10.1007/BF02967037 [PubMed] [CrossRef] [Google Scholar]102. Imai S. Mouse mammary tumor virus and mammary tumorigenesis in wild mice. Pathol Int (1996) 46:919–32. 10.1111/j.1440-1827.1996.tb03570.x [PubMed] [CrossRef] [Google Scholar]103. Rongey RW, Hlavackova A, Lara S, Estes J, Gardner MB.
Types B and C RNA virus in breast tissue and milk of wild mice. J Natl Cancer Inst (1973) 50:1581–9. 10.1093/jnci/50.6.1581 [PubMed] [CrossRef] [Google Scholar]104. Keydar I, Mesa-Tejada R, Ramanarayanan M, Ohno T, Fenoglio C, Hu R, et al.
Detection of viral proteins in mouse mammary tumors by immunoperoxidase staining of paraffin sections. Proc Natl Acad Sci U S A (1978) 75:1524–8. 10.1073/pnas.75.3.1524 [PMC free article] [PubMed] [CrossRef] [Google Scholar]105. Arthur LO, Bauer RF, Orme LS, Fine DL.
Coexistence of the mouse mammary tumor virus (MMTV) major glycoprotein and natural antibodies to MMTV in sera of mammary tumor-bearing mice. Virology (1978) 87:266–75. 10.1016/0042-6822(78)90132-0 [PubMed] [CrossRef] [Google Scholar]106. Haga S, Imai S, Morimoto J, Okumoto M, Iwai M, Iwai Y, et al.
Mouse mammary tumor virus proviral integration in the DD/Tbr Mice. Breast Cancer (1994) 1:11–6. 10.1007/BF02967369 [PubMed] [CrossRef] [Google Scholar]107. Lushnikova AA, Kryukova IN, Rotin DL, Lubchenko LN.
Detection of the env MMTV-homologous sequences in mammary carcinoma patient intestine lymphoid tissue. Dokl Biol Sci (2004) 399:423–6. 10.1007/s10630-005-0001-5 [PubMed] [CrossRef] [Google Scholar]108. Schwartz I, Levy D. Pathobiology of bovine leukemia virus. Vet Res (1994) 25:521–36. [PubMed] [Google Scholar]109. US Department of Agriculture Animal and Plant Health Services, Veterinary Services, Center for Epidemiology and Animal Health. Info Sheet: Bovine Leukosis Virus (BLV) on U.S. Dairy Operations – 2007. Riverdale, Maryland: U.S. Department of Agriculture; (2008). [Google Scholar]110. Gutiérrez G, Alvarez I, Politzki R, Lomónaco M, Dus Santos MJ, Rondelli F, et al.
Natural progression of bovine leukemia virus infection in Argentinean dairy cattle. Vet Microbiol (2011) 151:255–63. 10.1016/j.vetmic.2011.03.035 [PubMed] [CrossRef] [Google Scholar]111. Dairy Australia. (2012). Available from: http://www.dairyaustralia.com.au112. Giovanna M, Ulloa JC, Uribe AM, Gutierre MF.
Bovine leukemia virus gene segment detected in human breast tissue. Open J Med Microbiol (2013) 3:84–90. 10.4236/ojmm.2013.31013 [CrossRef] [Google Scholar]113. Buehring GC, Shen HM, Jensen HM, Choi KY, Sun D, Nuovo G. Bovine leukemia virus DNA in human breast tissue. Emerg Infect Dis (2014) 20:772–82. 10.3201/eid2005.131298 [PMC free article] [PubMed] [CrossRef] [Google Scholar]114. Buehring GC, Shen HM, Jensen HM, Jin DL, Hudes M, Block G. Exposure to bovine leukemia virus is associated with breast cancer: a case-control study. PLoS One (2015) 10:e0134304. 10.1371/journal.pone.0134304 [PMC free article] [PubMed] [CrossRef] [Google Scholar]115. Buehring GC, Shen H, Schwartz DA, Lawson JS. Bovine leukemia virus linked to breast cancer in Australian women and identified before breast cancer development. PLoS One (2017) 12:e0179367. 10.1371/journal.pone.0179367 [PMC free article] [PubMed] [CrossRef] [Google Scholar]116. Baltzell KA, Shen HM, Krishnamurty S, Sison JD, Nuovo GJ, Buehring GC.
Bovine leukemia virus linked to breast cancer but not coinfection with human papillomavirus: case-control study of women in Texas. Cancer (2017). 10.1002/cncr.31169 [PubMed] [CrossRef] [Google Scholar]117. Altaner C, Altanerová V, Bán J, Niwa O, Yokoro K. Human cells of neural origin are permissive for bovine leukemia virus. Neoplasma (1989) 36:691–5. [PubMed] [Google Scholar]118. Gillet NA, Willems L. Whole genome sequencing of 51 breast cancers reveals that tumors are devoid of bovine leukemia virus DNA. Retrovirology (2016) 13:75. 10.1186/s12977-016-0308-3 [PMC free article] [PubMed] [CrossRef] [Google Scholar]119. Buehring GC, Philpott SM, Choi KY. Humans have antibodies reactive with Bovine leukemia virus. AIDS Res Hum Retroviruses (2003) 19:1105–13. 10.1089/088922203771881202 [PubMed] [CrossRef] [Google Scholar]120. Zhang R, Jiang J, Sun W, Zhang J, Huang K, Gu X, et al.
Lack of association between bovine leukemia virus and breast cancer in Chinese patients. Breast Cancer Res (2016) 18:101. 10.1186/s13058-016-0763-8 [PMC free article] [PubMed] [CrossRef] [Google Scholar]121. Buehring GC.
Response to “lack of association between bovine leukemia virus and breast cancer in Chinese patients”. Breast Cancer Res (2017) 19(1):24. 10.1186/s13058-017-0808-7 [PMC free article] [PubMed] [CrossRef] [Google Scholar]122. zur Hausen H, de Villiers EM. Dairy cattle serum and milk factors contributing to the risk of colon and breast cancers. Int J Cancer (2015) 137:959–67. 10.1002/ijc.29466 [PubMed] [CrossRef] [Google Scholar]123. Ji J, Sundquist J, Sundquist K. Lactose intolerance and risk of lung, breast and ovarian cancers: aetiological clues from a population-based study in Sweden. Br J Cancer (2015) 112:149–52. 10.1038/bjc.2014.544 [PMC free article] [PubMed] [CrossRef] [Google Scholar]124. Michels KB, Ekbom A. Caloric restriction and incidence of breast cancer. JAMA (2004) 291(10):1226–30. 10.1001/jama.291.10.1226 [PubMed] [CrossRef] [Google Scholar]125. Morimoto LM, Newcomb PA, White E, Bigler J, Potter JD. Variation in plasma insulin-like growth factor-1 and insulin-like growth factor binding protein-3: personal and lifestyle factors (United States). Cancer Causes Control (2005) 16(8):917–27. 10.1007/s10552-005-2702-3 [PubMed] [CrossRef] [Google Scholar]126. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al.
Diet rapidly and reproducibly alters the human gut microbiome. Nature (2014) 505(7484):559–63. 10.1038/nature12820 [PMC free article] [PubMed] [CrossRef] [Google Scholar]127. Wada K, Nakamura K, Tamai Y, Tsuji M, Kawachi T, Hori A, et al.
Soy isoflavone intake and breast cancer risk in Japan: from the Takayama study. Int J Cancer (2013) 133:952–60. 10.1002/ijc.28088 [PubMed] [CrossRef] [Google Scholar]128. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al.
Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer (2015) 136:E359–86. 10.1002/ijc.29210 [PubMed] [CrossRef] [Google Scholar]129. Choi J, Kim C, Lee HS, Choi YJ, Kim HY, Lee J, et al.
Detection of human papillomavirus in Korean breast cancer patients by real-time polymerase chain reaction and meta-analysis of human papillomavirus and breast cancer. J Pathol Transl Med (2016) 50:442–50. 10.4132/jptm.2016.07.08 [PMC free article] [PubMed] [CrossRef] [Google Scholar]130. Bae JM, Kim EH. Human papillomavirus infection and risk of breast cancer: a meta-analysis of case-control studies. Infect Agent Cancer (2016) 11:14. 10.1186/s13027-016-0058-9 [PMC free article] [PubMed] [CrossRef] [Google Scholar]131. Yu Y, Morimoto T, Sasa M, Okazaki K, Harada Y, Fujiwara T, et al.
HPV33 DNA in premalignant and malignant breast lesions in Chinese and Japanese populations. Anticancer Res (1999) 19(6B):5057–61. [PubMed] [Google Scholar]132. Damin AP, Karam R, Zettler CG, Caleffi M, Alexandre CO. Evidence for an association of human papillomavirus and breast carcinomas. Breast Cancer Res Treat (2004) 84:131–7. 10.1023/B:BREA.0000018411.89667.0d [PubMed] [CrossRef] [Google Scholar]133. Tsai JH, Tsai CH, Cheng MH, Lin SJ, Xu FL, Yang CC. Association of viral factors with non-familial breast cancer in Taiwan by comparison with non-cancerous, fibroadenoma, and thyroid tumor tissues. J Med Virol (2005) 75:276–81. 10.1002/jmv.20267 [PubMed] [CrossRef] [Google Scholar]134. Choi YL, Cho EY, Kim JH, Nam SJ, Oh YL, Song SY, et al.
Detection of human papillomavirus DNA by DNA chip in breast carcinomas of Korean women. Tumour Biol (2007) 28:327–32. 10.1159/000124238 [PubMed] [CrossRef] [Google Scholar]135. Gumus M, Yumuk PF, Salepci T, Aliustaoglu M, Dane F, Ekenel M, et al.
HPV DNA frequency and subset analysis in human breast cancer patients’ normal and tumoral tissue samples. J Exp Clin Cancer Res (2006) 25:515–21. [PubMed] [Google Scholar]136. He Q, Zhang SQ, Chu YL, Jia XL, Wang XL. The correlations between HPV16 infection and expressions of c-erbB-2 and bcl-2 in breast carcinoma. Mol Biol Rep (2009) 36:807–12. 10.1007/s11033-008-9249-9 [PubMed] [CrossRef] [Google Scholar]137. de León DC, Montiel DP, Nemcova J, Mykyskova I, Turcios E, Villavicencio V, et al.
Human papillomavirus (HPV) in breast tumors: prevalence in a group of Mexican patients. BMC Cancer (2009) 9:26. 10.1186/1471-2407-9-26 [PMC free article] [PubMed] [CrossRef] [Google Scholar]138. Heng B, Glenn WK, Ye Y, Tran B, Delprado W, Lutze-Mann L, et al.
Human papilloma virus is associated with breast cancer. Br J Cancer (2009) 101:1345–50. 10.1038/sj.bjc.6605282 [PMC free article] [PubMed] [CrossRef] [Google Scholar]139. Herrera-Goepfert R, Khan NA, Koriyama C, Akiba S, Pérez-Sánchez VM. High-risk human papillomavirus in mammary gland carcinomas and non-neoplastic tissues of Mexican women: no evidence supporting a cause and effect relationship. Breast (2011) 20:184–9. 10.1016/j.breast.2010.11.006 [PubMed] [CrossRef] [Google Scholar]140. Mou X, Chen L, Liu F, Shen Y, Wang H, Li Y, et al.
Low prevalence of human papillomavirus (HPV) in Chinese patients with breast cancer. J Int Med Res (2011) 39:1636–44. 10.1177/147323001103900506 [PubMed] [CrossRef] [Google Scholar]141. Chang P, Wang T, Yao Q, Lv Y, Zhang J, Guo W, et al.
Absence of human papillomavirus in patients with breast cancer in north-west China. Med Oncol (2012) 29:521–5. 10.1007/s12032-011-9945-5 [PubMed] [CrossRef] [Google Scholar]142. Sigaroodi A, Nadji SA, Naghshvar F, Nategh R, Emami H, Velayati AA. Human papillomavirus is associated with breast cancer in the north part of Iran. ScientificWorldJournal (2012) 2012:837191. 10.1100/2012/837191 [PMC free article] [PubMed] [CrossRef] [Google Scholar]143. Frega A, Lorenzon L, Bononi M, De Cesare A, Ciardi A, Lombardi D, et al.
Evaluation of E6 and E7 mRNA expression in HPV DNA positive breast cancer. Eur J Gynaecol Oncol (2012) 33:164–7. [PubMed] [Google Scholar]144. Liang W, Wang J, Wang C, Lv Y, Gao H, Zhang K, et al.
Detection of high-risk human papillomaviruses in fresh breast cancer samples using the hybrid capture 2 assay. J Med Virol (2013) 85:2087–92. 10.1002/jmv.23703 [PubMed] [CrossRef] [Google Scholar]145. Ahangar Oskouee M, Shahmahmoodi S, Jalilvand S, Mahmoodi M, Ziaee AA, Esmaeili HA, et al.
No evidence of mammary tumor virus env gene-like sequences among Iranian women with breast cancer. Intervirology (2014) 57:353–6. 10.1159/000366280 [PubMed] [CrossRef] [Google Scholar]146. Ali SH, Al-Alwan NA, Al-Alwany SH. Detection and genotyping of human papillomavirus in breast cancer tissues from Iraqi patients. East Mediterr Health J (2014) 20:372–7. [PubMed] [Google Scholar]147. Manzouri L, Salehi R, Shariatpanahi S, Rezaie P. Prevalence of human papilloma virus among women with breast cancer since 2005-2009 in Isfahan. Adv Biomed Res (2014) 3:75. 10.4103/2277-9175.125873 [PMC free article] [PubMed] [CrossRef] [Google Scholar]148. Peng J, Wang T, Zhu H, Guo J, Li K, Yao Q, et al.
Multiplex PCR/mass spectrometry screening of biological carcinogenic agents in human mammary tumors. J Clin Virol (2014) 61:255–9. 10.1016/j.jcv.2014.07.010 [PubMed] [CrossRef] [Google Scholar]149. Fu L, Wang D, Shah W, Wang Y, Zhang G, He J. Association of human papillomavirus type 58 with breast cancer in Shaanxi province of China. J Med Virol (2015) 87:1034–40. 10.1002/jmv.24142 [PubMed] [CrossRef] [Google Scholar]150. Li J, Ding J, Zhai K. Detection of human papillomavirus DNA in patients with breast tumor in China. PLoS One (2015) 10:e0136050. 10.1371/journal.pone.0136050 [PMC free article] [PubMed] [CrossRef] [Google Scholar]151. Wang D, Fu L, Shah W, Zhang J, Yan Y, Ge X, et al.
Presence of high risk HPV DNA but indolent transcription of E6/E7 oncogenes in invasive ductal carcinoma of breast. Pathol Res Pract (2016) 212:1151–6. 10.1016/j.prp.2016.09.009 [PubMed] [CrossRef] [Google Scholar]152. Delgado-García S, Martínez-Escoriza JC, Alba A, Martín-Bayón TA, Ballester-Galiana H, Peiró G, et al.
Presence of human papillomavirus DNA in breast cancer: a Spanish case-control study. BMC Cancer (2017) 17:320. 10.1186/s12885-017-3308-3 [PMC free article] [PubMed] [CrossRef] [Google Scholar]153. Salman NA, Davies G, Majidy F, Shakir F, Akinrinade H, Perumal D, et al.
Association of high risk human papillomavirus and breast cancer: a UK based Study. Sci Rep (2017) 7:43591. 10.1038/srep43591 [PMC free article] [PubMed] [CrossRef] [Google Scholar]154. Labrecque LG, Barnes DM, Fentiman IS, Griffin BE. Epstein-Barr virus in epithelial cell tumors: a breast cancer study. Cancer Res (1995) 55:39–45. [PubMed] [Google Scholar]155. Bonnet M, Guinebretiere JM, Kremmer E, Grunewald V, Benhamou E, Contesso G, et al.
Detection of Epstein-Barr virus in invasive breast cancers. J Natl Cancer Inst (1999) 91:1376–81. 10.1093/jnci/91.16.1376 [PubMed] [CrossRef] [Google Scholar]156. Grinstein S, Preciado MV, Gattuso P, Chabay PA, Warren WH, De Matteo E, et al.
Demonstration of Epstein-Barr virus in carcinomas of various sites. Cancer Res (2002) 62:4876–8. [PubMed] [Google Scholar]157. Preciado MV, Chabay PA, De Matteo EN, Gonzalez P, Grinstein S, Actis A, et al.
Epstein-Barr virus in breast carcinoma in Argentina. Arch Pathol Lab Med (2005) 129:377–81. 10.1043/1543-2165(2005)129<377:EVIBCI>2.0.CO;2 [PubMed] [CrossRef] [Google Scholar]158. Fawzy S, Sallam M, Awad NM. Detection of Epstein-Barr virus in breast carcinoma in Egyptian women. Clin Biochem (2008) 41:486–92. 10.1016/j.clinbiochem.2007.12.017 [PubMed] [CrossRef] [Google Scholar]159. Joshi D, Quadri M, Gangane N, Joshi R, Gangane N. Association of Epstein Barr virus infection (EBV) with breast cancer in rural Indian women. PLoS One (2009) 4:e8180. 10.1371/journal.pone.0008180 [PMC free article] [PubMed] [CrossRef] [Google Scholar]160. Lorenzetti MA, De Matteo E, Gass H, Martinez Vazquez P, Lara J, Gonzalez P, et al.
Characterization of Epstein Barr virus latency pattern in Argentine breast carcinoma. PLoS One (2010) 5:e13603. 10.1371/journal.pone.0013603 [PMC free article] [PubMed] [CrossRef] [Google Scholar]161. Zekri AR, Bahnassy AA, Mohamed WS, El-Kassem FA, El-Khalidi SJ, Hafez MM, et al.
Epstein-Barr virus and breast cancer: epidemiological and molecular study on Egyptian and Iraqi women. J Egypt Natl Canc Inst (2012) 24:123–31. 10.1016/j.jnci.2012.06.001 [PubMed] [CrossRef] [Google Scholar]162. Yahia ZA, Adam AA, Elgizouli M, Hussein A, Masri MA, Kamal M, et al.
Epstein Barr virus: a prime candidate of breast cancer aetiology in Sudanese patients. Infect Agent Cancer (2014) 9:9. 10.1186/1750-9378-9-9 [PMC free article] [PubMed] [CrossRef] [Google Scholar]163. El-Naby NEH, Hassan Mohamed H, Mohamed Goda A, El Sayed Mohamed A. Epstein-Barr virus infection and breast invasive ductal carcinoma in Egyptian women: a single center experience. J Egypt Natl Canc Inst (2017) 29:77–82. 10.1016/j.jnci.2017.02.002 [PubMed] [CrossRef] [Google Scholar]164. Pai T, Gupta S, Gurav M, Nag S, Shet T, Patil A, et al.
Evidence for the association of Epstein-Barr virus in breast cancer in Indian patients using in-situ hybridization technique. Breast J (2017). 10.1111/tbj.12828 [PubMed] [CrossRef] [Google Scholar]165. Yan C, Teng ZP, Chen YX, Shen DH, Li JT, Zeng Y. Viral etiology relationship between human papillomavirus and human breast cancer and target of gene therapy. Biomed Environ Sci (2016) 29:331–9. 10.3967/bes2016.043 [PubMed] [CrossRef] [Google Scholar]166. Lawson JS, Glenn WK, Salyakina D, Delprado W, Clay R, Antonsson A, et al.
Human papilloma viruses and breast cancer. Front Oncol (2015) 5:277. 10.3389/fonc.2015.00277 [PMC free article] [PubMed] [CrossRef] [Google Scholar]167. Lawson JS, Glenn WK, Heng B, Ye Y, Tran B, Lutze-Mann L, et al.
Koilocytes indicate a role for human papilloma virus in breast cancer. Br J Cancer (2009) 101:1351–6. 10.1038/sj.bjc.6605328 [PMC free article] [PubMed] [CrossRef] [Google Scholar]168. Gannon OM, Antonsson A, Milevskiy M, Brown MA, Saunders NA, Bennett IC. No association between HPV positive breast cancer and expression of human papilloma viral transcripts. Sci Rep (2015) 5:18081. 10.1038/srep18081 [PMC free article] [PubMed] [CrossRef] [Google Scholar]169. Lawson JS, Glenn WK, Salyakina D, Clay R, Delprado W, Cheerala B, et al.
Human papilloma virus identification in breast cancer patients with previous cervical neoplasia. Front Oncol (2016) 5:298. 10.3389/fonc.2015.00298 [PMC free article] [PubMed] [CrossRef] [Google Scholar]170. Atique S, Hsieh CH, Hsiao RT, Iqbal U, Nguyen PAA, Islam MM, et al.
Viral warts (human papilloma virus) as a potential risk for breast cancer among younger females. Comput Methods Programs Biomed (2017) 144:203–7. 10.1016/j.cmpb.2017.03.024 [PubMed] [CrossRef] [Google Scholar]171. Dimri G, Band H, Band V. Mammary epithelial cell transformation: insights from cell culture and mouse models. Breast Cancer Res (2005) 7:171–9. 10.1186/bcr973 [PMC free article] [PubMed] [CrossRef] [Google Scholar]172. Yasmeen A, Bismar TA, Kandouz M, Foulkes WD, Desprez PY, Al Moustafa AE. E6/E7 of HPV type 16 promotes cell invasion and metastasis of human breast cancer cells. Cell Cycle (2007) 6:2038–42. 10.4161/cc.6.16.4555 [PubMed] [CrossRef] [Google Scholar]173. Lawson JS, Glenn WK, Whitaker NJ.
Breast cancer, human papilloma virus and sexual activities. Br J Cancer (2008) 98:510–1. 10.1038/sj.bjc.6604104 [CrossRef] [Google Scholar]174. Foresta C, Bertoldo A, Garolla A, Pizzol D, Mason S, Lenzi A, et al.
Human papillomavirus proteins are found in peripheral blood and semen Cd20+ and Cd56+ cells during Hpv-16 semen infection. BMC Infect Dis (2013) 13:593. 10.1186/1471-2334-13-593 [PMC free article] [PubMed] [CrossRef] [Google Scholar]175. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet (2007) 370:59–67. 10.1016/S0140-6736(07)61050-2 [PubMed] [CrossRef] [Google Scholar]176. Ngan C, Lawson JS, Clay R, Delprado W, Whitaker NJ, Glenn WK. Early human papilloma virus (HPV) oncogenic influences in breast cancer. Breast Cancer (Auckl) (2015) 9:93–7. 10.4137/BCBCR.S35692 [PMC free article] [PubMed] [CrossRef] [Google Scholar]177. Al Moustafa AE, Al-Antary N, Aboulkassim T, Akil N, Batist G, Yasmeen A. Co-prevalence of Epstein-Barr virus and high-risk human papillomaviruses in Syrian women with breast cancer. Hum Vaccin Immunother (2016) 12:1936–9. 10.1080/21645515.2016.1139255 [PMC free article] [PubMed] [CrossRef] [Google Scholar]178. Corbex M, Bouzbid S, Traverse-Glehen A, Aouras H, McKay-Chopin S, Carreira C, et al.
Prevalence of papillomaviruses, polyomaviruses, and herpesviruses in triple-negative and inflammatory breast tumors from algeria compared with other types of breast cancer tumors. PLoS One (2014) 9:e114559. 10.1371/journal.pone.0114559 [PMC free article] [PubMed] [CrossRef] [Google Scholar]179. Cameron J.
HPV and EBV collaboration. DNA Tumour Virus Meeting Abstracts. Trieste: International Centre for Genetic Engineering and Biotechnology; (2011). [Google Scholar]180. Richardson AK, Currie MJ, Robinson BA, Morrin H, Phung Y, Pearson JF, et al.
Cytomegalovirus and Epstein-Barr virus in breast cancer. PLoS One (2015) 10:e0118989. 10.1371/journal.pone.0118989 [PMC free article] [PubMed] [CrossRef] [Google Scholar]181. Cox B, Richardson A, Graham P, Gislefoss RE, Jellum E, Rollag H.
Breast cancer, cytomegalovirus and Epstein–Barr virus: a nested case–control study. Br J Cancer (2010) 102:1665–9. 10.1038/sj.bjc.6605675 [PMC free article] [PubMed] [CrossRef] [Google Scholar]182. He JR, Tang LY, Yu DD, Su FX, Song EW, Lin Y, et al.
Epstein-Barr virus and breast cancer: serological study in a high-incidence area of nasopharyngeal carcinoma. Cancer Lett (2011) 309:128–36. 10.1016/j.canlet.2011.05.012 [PubMed] [CrossRef] [Google Scholar]183. Yasui Y, Potter JD, Stanford JL, Rossing MA, Winget MD, Bronner M, et al.
Breast cancer risk and “delayed” primary Epstein-Barr virus infection. Cancer Epidemiol Biomarkers Prev (2001) 10:9–16. [PubMed] [Google Scholar]184. Zhang W, Wang MY, Wei XL, Lin Y, Su FX, Xie XM, et al.
Associations of Epstein-Barr virus DNA in PBMCs and the subtypes with breast cancer risk. J Cancer (2017) 8(15):2944–9. 10.7150/jca.20330 [PMC free article] [PubMed] [CrossRef] [Google Scholar]185. Lawson JS, Glenn WK. Multiple oncogenic viruses are present in human breast tissues before development of virus associated breast cancer. Infect Agent Cancer (2017) 12:55. 10.1186/s13027-017-0165-2 [PMC free article] [PubMed] [CrossRef] [Google Scholar]186. Speck P, Longnecker R.
Infection of breast epithelial cells with Epstein-Barr virus via cell-to-cell contact. J Natl Cancer Inst (2000) 92:1849–51. 10.1093/jnci/92.22.1849 [PubMed] [CrossRef] [Google Scholar]187. Hu H, Luo ML, Desmedt C, Nabavi S, Yadegarynia S, Hong A, et al.
Epstein-Barr virus infection of mammary epithelial cells promotes malignant transformation. EBioMedicine (2016) 9:148–60. 10.1016/j.ebiom.2016.05.025 [PMC free article] [PubMed] [CrossRef] [Google Scholar]188. Polz-Dacewicz M, Strycharz-Dudziak M, Dworzanski J, Stec A, Kocot J.
Salivary and serum IL-10, TNF-alpha, TGF-beta, VEGF levels in oropharyngeal squamous cell carcinoma and correlation with HPV and EBV infections. Infect Agent Cancer (2016) 11:45. 10.1186/s13027-016-0093-6 [PMC free article] [PubMed] [CrossRef] [Google Scholar]189. Szostek S, Zawilinska B, Kopec J, Kosz-Vnenchak M. Herpesviruses as possible cofactors in HPV-16-related oncogenesis. Acta Biochim Pol (2009) 56:337–42. [PubMed] [Google Scholar]190. Perzova R, Abbott L, Benz P, Landas S, Khan S, Glaser J, et al.
Is MMTV associated with human breast cancer? Maybe, but probably not. Virol J (2017) 14(1):196. 10.1186/s12985-017-0862-x [PMC free article] [PubMed] [CrossRef] [Google Scholar]191. Holland JF, Pogo BG.
Comment on the review by Joshi and Buehring. Breast Cancer Res Treat (2012) 136(1):303–7. 10.1007/s10549-012-2078-5 [PubMed] [CrossRef] [Google Scholar]192. Tang KW, Larsson E.
Tumour virology in the era of high-throughput genomics. Philos Trans R Soc Lond B Biol Sci (1732) 2017:372. [PMC free article] [PubMed] [Google Scholar]193. Fimereli D, Gacquer D, Fumagalli D, Salgado R, Rothé F, Larsimont D, et al.
No significant viral transcription detected in whole breast cancer transcriptomes. BMC Cancer (2015) 15:147. 10.1186/s12885-015-1176-2 [PMC free article] [PubMed] [CrossRef] [Google Scholar]194. Burton DS, Blair PB, Weiss DW.
Protection against mammary tumors in mice by immunization with purified mammary tumor virus preparations. Cancer Res (1969) 29:971–3. [PubMed] [Google Scholar]195. Sarkar NH, Moore DH. Immunization of mice against murine mammary tumor virus infection and mammary tumor development. Cancer Res (1978) 38:1468–72. [PubMed] [Google Scholar]196. Mpandi M, Otten LA, Lavanchy C, Acha-Orbea H, Finke D. Passive immunization with neutralizing antibodies interrupts the mouse mammary tumor virus life cycle. J Virol (2003) 77:9369–77. 10.1128/JVI.77.17.9369-9377.2003 [PMC free article] [PubMed] [CrossRef] [Google Scholar]197. Astori M, Karapetian O. Immunization with a mouse mammary tumour virus envelope protein epitope protects against tumour formation without inhibition of the virus infection. J Gen Virol (1997) 78:1935–9. 10.1099/0022-1317-78-8-1935 [PubMed] [CrossRef] [Google Scholar]198. Braitbard O, Roniger M, Bar-Sinai A, Rajchman D, Gross T, Abramovitch H, et al.
A new immunization and treatment strategy for mouse mammary tumor virus (MMTV) associated cancers. Oncotarget (2016) 7:21168–80. 10.18632/oncotarget.7762 [PMC free article] [PubMed] [CrossRef] [Google Scholar]199. Evermann J.
Cause for concern: bovine leukemia virus. Veterinary Medicine Extension. (2014). p. 1–5. Available from: http://vetextension.wsu.edu/wp-content/uploads/sites/8/2015/03/BovineLeukemiaVirus_June2014.pdf200. Weigelt B, Horlings HM, Kreike B, Hayes MM, Hauptmann M, Wessels LF, et al.
Refinement of breast cancer classification by molecular characterization of histological special types. J Pathol (2008) 216:141–50. 10.1002/path.2407 [PubMed] [CrossRef] [Google Scholar]201. Lawson JS, Ngan CC, Glenn WK, Tran DD. Mouse mammary tumour virus (MMTV) and human breast cancer with neuroendocrine differentiation. Infect Agent Cancer (2017) 12:24. 10.1186/s13027-017-0135-8 [PMC free article] [PubMed] [CrossRef] [Google Scholar]202. Aloraifi F, Boland MR, Green AJ, Geraghty JG.
Gene analysis techniques and susceptibility gene discovery in non-BRCA1/BRCA2 familial breast cancer. Surg Oncol (2015) 24(2):100–9. 10.1016/j.suronc.2015.04.003 [PubMed] [CrossRef] [Google Scholar]203. Chandler MR, Bilgili EP, Merner ND. A review of whole-exome sequencing efforts toward hereditary breast cancer susceptibility gene discovery. Hum Mutat (2016) 37(9):835–46. 10.1002/humu.23017 [PubMed] [CrossRef] [Google Scholar]204. Cobain EF, Milliron KJ, Merajver SD. Updates on breast cancer genetics: clinical implications of detecting syndromes of inherited increased susceptibility to breast cancer. Semin Oncol (2016) 43(5):528–35. 10.1053/j.seminoncol.2016.10.001 [PubMed] [CrossRef] [Google Scholar]205. Finlay-Schultz J, Sartorius CA. Steroid hormones, steroid receptors, and breast cancer stem cells. J Mammary Gland Biol Neoplasia (2015) 20(1–2):39–50. 10.1007/s10911-015-9340-5 [PMC free article] [PubMed] [CrossRef] [Google Scholar]206. Bozorgi A, Khazaei M, Khazaei MR. New findings on breast cancer stem cells: a review. J Breast Cancer (2015) 18(4):303–12. 10.4048/jbc.2015.18.4.303 [PMC free article] [PubMed] [CrossRef] [Google Scholar]Articles from Frontiers in Oncology are provided here courtesy of Frontiers Media SA
Other Formats
PDF (245K)
Actions
Cite
Collections
Add to Collections
Create a new collection
Add to an existing collection
Name your collection:
Name must be less than characters
Choose a collection:
Unable to load your collection due to an error
Please try again
Add
Cancel
Share
Permalink
Copy
RESOURCES
Similar articles
Cited by other articles
Links to NCBI Databases
[x]
Cite
Copy
Download .nbib
.nbib
Format:
AMA
APA
MLA
NLM
Follow NCBI
GitHub
Connect with NLM
SM-Twitter
SM-Facebook
SM-Youtube
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
Web Policies
FOIA
HHS Vulnerability Disclosure
Help
Accessibility
Careers
NLM
NIH
HHS
USA.gov