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，癌症可以在出生前开始。子宫内暴露于激素干扰物己烯雌酚（DES）与以后生活中乳腺癌风险增加有关，其机制尚不清楚。BPA是一种常见的环境化学品，具有雌激素性质。围产期暴露于BPA相关的乳腺癌风险正在成为一个严重的健康问题。以往使用致癌物模型的研究表明，围产期暴露于BPA诱导前雌激素效应在成年早期阶段，并促进乳腺肿瘤的发展，在这些动物，但这些影响的详细机制尚不清楚。我们一直在使用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剂染料木黄酮或BPA促进乳腺肿瘤的发展，在以后的生活中，这是之前的显着改变组织结构和信号在雌激素受体（ER）和erbB-2途径在成年腺体。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/祖细胞的再增殖。为了研究子宫内暴露于BPA相关乳腺肿瘤风险的分子机制，我们假设子宫内暴露于BPA通过诱导ER-erbB-2串扰和乳腺干细胞重编程增加erbB-2转基因小鼠的乳腺癌风险。具体目标是：1）研究BPA在子宫内暴露对erbB-2通路的激活作用以及ER与erbB-2通路之间的相互作用。将使用功能基因组学分析ER-DNA结合模式的修饰。2）。通过流式细胞术分析干细胞标志物和乳腺移植，确定子宫内暴露于BPA对乳腺干/祖细胞重编程的影响。有了这种临床相关的小鼠模型和新方法，该项目的结果预计将对乳腺癌的预防和管理产生重大影响。

 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.