A Multistage Murine Breast Cancer Model Reveals Long-Lived Premalignant Clones Refractory to Parity-Induced Protection.
A Multistage Murine Breast Cancer Model Reveals Long-Lived Premalignant Clones Refractory to Parity-Induced Protection.
复制标题
多阶段小鼠乳腺癌模型揭示了对奇偶诱导保护无效的长寿命癌前克隆。
DOI：
10.1158/1940-6207.capr-19-0322
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Gunther,EdwardJ
中科院分区：
文献类型：
--
作者：
Li,Shuo;Gestl,ShelleyA;Gunther,EdwardJ
乳腺癌的演变是一个多阶段的过程，在致癌暴露后可能会持续数十年。由此得出的结论是，长期存活的前驱乳腺病变在完成恶变之前一直处于亚临床状态，但广泛使用的乳腺癌模型缺乏针对癌前疾病的实验框架。受经典的多阶段皮肤癌变方案的启发，我们将化学致癌与转基因小鼠模型相结合，将小鼠乳腺癌的发生分为离散的起始和进展阶段。在启动阶段，暴露于致癌物7，12-二甲基苯并蒽(DMBA)中，通过引入立体型HrasQ61L驱动突变，产生“启动的乳房上皮细胞”(IMEC)。无论DMBA暴露发生在青春期还是成年期，小鼠都有效地获得了传统组织学无法检测到的iMEC克隆，但它们活了很长时间，在没有合作事件的情况下，在临床上保持了几个月的沉默状态。在进展阶段，致癌基因Wnt信号的可诱导激活驱动潜伏的iMECs快速而同步地转化为显性乳腺癌，而在同一时期，邻近正常乳腺上皮中的Wnt激活仅产生良性增生。尽管早产(足月妊娠完成)在某些情况下降低了乳腺癌的风险，但在我们的多阶段模型中，标准的产次诱导保护方案未能消除iMEC，这表明Wnt反应的iMEC是由激素无关的机制维持的。我们的多阶段建模策略的变化可能有助于识别和验证乳腺癌化学预防的细胞和分子靶点。
Breast cancers evolve in a multistage process that can span decades after a carcinogenic exposure. It follows that long-lived precursor breast lesions persist in a subclinical state prior to completing malignant transformation, yet widely used breast cancer models lack an experimental framework for targeting premalignant disease. Inspired by classic multistage skin carcinogenesis protocols, we combined chemical carcinogenesis with transgenic mouse modeling to resolve mouse mammary carcinogenesis into discrete initiation and progression stages. At the initiation stage, exposure to the carcinogen 7,12-dimethylbenzanthracene (DMBA) generated “initiated mammary epithelial cells” (iMEC) by introducing a stereotypedHrasQ61Ldriver mutation. Whether DMBA exposure occurred during puberty or adulthood, mice efficiently acquired iMEC clones that eluded detection by conventional histology, yet were long lived, persisting in a clinically silent state for months in the absence of a cooperating event. At the progression stage, inducible activation of oncogenic Wnt signaling drove rapid and synchronous transformation of latent iMECs into overt mammary carcinomas, while Wnt activation in neighboring normal mammary epithelium yielded only benign hyperplasia over this same time period. Although early parity (completion of a full-term pregnancy) reduces breast cancer risk in some contexts, standard parity-induced protection schemes failed to eliminate iMECs in our multistage model, suggesting Wnt-responsive iMECs are maintained by hormone-independent mechanisms. Variations on our multistage modeling strategy may help to identify and validate cellular and molecular targets for breast cancer chemoprevention.