Mechanisms of in utero exposure to bisphenol A induced mammary tumor risk

 描述(由申请人提供)：越来越多的证据表明，癌症可能在出生前就开始了。子宫内暴露于激素干扰物己烯雌酚(DES)与乳腺癌风险增加有关，其机制尚不清楚。双酚A是一种常见的具有雌激素性质的环境化学品。围产期暴露于双酚A相关的乳腺癌风险正在成为一个严重的健康问题。以前的致癌模型研究表明，围产期暴露于BPA可在成年早期诱导雌激素效应，并促进这些动物的乳腺肿瘤的发展，但这些效应的详细机制尚不清楚。我们一直在利用MMTV-erbB-2转基因模型研究erbB-2介导的乳腺癌风险的激素调节。我们证明，在子宫内暴露于激素干扰物Genistein或BPA可促进成年后乳腺肿瘤的发展，在此之前，成年腺体中雌激素受体(ER)和erbB-2通路的组织结构和信号都发生了显著变化。我们的数据还表明，在子宫内暴露于激素干扰物可能会诱导乳腺干细胞/祖细胞的重新繁殖。为了探讨宫内暴露于双酚A相关乳腺癌风险的分子机制，我们假设宫内暴露于双酚A可通过诱导ER-erbB-2串扰和乳腺干细胞重编程来增加erbB-2转基因小鼠的乳腺癌风险。其具体目的是：1)研究子宫内暴露于双酚A诱导的erbB-2信号通路的激活以及ER和erbB-2信号通路之间的串扰。ER-DNA结合模式的修饰将使用功能基因组学进行分析。2)。通过流式细胞仪分析干细胞标志物和乳腺移植，探讨宫内暴露双酚A对乳腺干/祖细胞重编程的影响。随着这一具有临床意义的小鼠模型和新方法的出现，该项目的结果有望对乳腺癌的预防和治疗产生重大影响。

 DESCRIPTION (provided by applicant): Increasing evidence indicates that cancer can start before birth. In utero exposure to hormonal disruptor diethylstilbestrol (DES) has been associated with increased breast cancer risk in later life by unknown mechanisms. BPA is a common environmental chemical with estrogenic properties. Perinatal exposure to BPA associated breast cancer risk is emerging as a serious health concern. Previous studies using carcinogen models indicate that perinatal exposure to BPA induces proestrogenic effect in early adult stage and promotes mammary tumor development in these animals, but detailed mechanisms of these effects remain unclear. We have been studying hormonal modulation of erbB-2 mediated breast cancer risk using the MMTV-erbB-2 transgenic model. We demonstrated that in utero exposure to hormonal disruptor genistein or BPA promoted mammary tumor development in later life, which was preceded with significantly altered histoarchitectures and signaling in both estrogen receptor (ER) and erbB-2 pathways in the adult glands. Our data also suggest that in utero exposure to hormonal disruptors may induce the repopulation of mammary stem/progenitor cells. To investigate the molecular mechanisms of in utero exposure to BPA associated mammary tumor risk, we hypothesize that in utero exposure to BPA increase mammary cancer risk of erbB-2 transgenic mice through the induction of ER-erbB-2 crosstalk and the reprogramming of mammary stem cells. The specific aims are: 1) To investigate in utero exposure to BPA induced activation of erbB-2 pathway and the crosstalk between ER and erbB-2 pathways. Modification of ER-DNA binding patterns will be analyzed using functional genomics. 2). To determine the effect of in utero exposure to BPA on the reprogramming of mammary stem/progenitor cells by flow cytometry analysis of stem cell markers and mammary gland transplantation. With this clinically relevant mouse model and novel approaches, the results from this project are expected to have significant impact on breast cancer prevention and management.