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

子宫内接触双酚 A 诱发乳腺肿瘤风险的机制

• 批准号: 9142323
• 负责人: XIAOHE YANG
• 金额: $ 22.06万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9142323
• 关键词: Address; Adult; Affect; Animal Model; Animals; Binding Proteins; Biological Assay; Birth; Breast Cancer Prevention; Cancer Etiology; Carcinogens; Cells; ChIP-seq; DNA Binding; Data; Development; Diethylstilbestrol; Disease; Dose; EGF gene; Elderly; Endocrine Disruptors; Epidermal Growth Factor Receptor; Epithelial; ErbB4 gene; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Exposure to; FVB Mouse; FVB/N Mouse; Family; Flow Cytometry; Gene Expression; Gene Targeting; Genetic Transcription; Genistein; Gland; Growth; Health; Hormonal; Human; Lead; Life; Ligands; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Measures; Mediating; Methylation; Modeling; Modification; Molecular; Morphogenesis; Mouse Mammary Tumor Virus; Mus; Pathway interactions; Pattern; Perinatal Exposure; Phosphorylation; Play; Predisposition; Pregnancy; Property; Puberty; Receptor Activation; Receptor Signaling; Risk; Risk Factors; Role; Serum; Signal Transduction; Staging; Stem cells; Technology; Testing; Tissues; Transgenic Mice; Transgenic Model; Transplantation; base; bisphenol A; cancer prevention; cancer risk; clinically relevant; environmental chemical; estrogenic; functional genomics; gene environment interaction; genome wide methylation; genome-wide; insight; lapatinib; malignant breast neoplasm; mammary gland development; mouse model; novel; novel strategies; offspring; overexpression; prenatal; progenitor; promoter; receptor binding; research study; response; stem; targeted agent; tumor

 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.

 描述（由申请人提供）：越来越多的证据表明，在子宫内接触激素干扰剂己烯雌酚 (DES) 会通过未知的机制增加患乳腺癌的风险。围产期接触 BPA 相关的乳腺癌风险正在成为一个严重的健康问题，之前使用致癌物模型的研究表明，围产期接触 BPA 会诱发孕激素效应。成年早期并促进这些动物乳腺肿瘤的发展，但这些作用的详细机制仍不清楚，我们一直在使用 MMTV-erbB-2 转基因模型研究激素调节 erbB-2 介导的乳腺癌风险。接触激素干扰物金雀异黄素或 BPA 会促进晚年乳腺肿瘤的发展，在此之前雌激素受体 (ER) 和我们的数据还表明，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，我们认识到这一点。子宫内接触 BPA 通过诱导 ER-erbB-2 串扰和乳腺重新编程，增加 erbB-2 转基因小鼠患乳腺癌的风险具体目标是： 1) 研究子宫内暴露于 BPA 诱导的 erbB-2 通路激活以及使用功能基因组学分析 ER 和 erbB-2 通路之间的串扰 2。通过干细胞标记物的流式细胞术分析和乳腺移植来确定子宫内接触 BPA 对乳腺干细胞/祖细胞重编程的影响。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。

项目成果

microRNA Regulation in Estrogen Receptor-Positive Breast Cancer and Endocrine Therapy.

• DOI: 10.1186/s12575-018-0082-9
• 发表时间: 2018
• 期刊: Biological procedures online
• 影响因子: 6.4
• 作者: Howard EW;Yang X
• 通讯作者: Yang X

Ganetespib targets multiple levels of the receptor tyrosine kinase signaling cascade and preferentially inhibits ErbB2-overexpressing breast cancer cells.

• DOI: 10.1038/s41598-018-25284-0
• 发表时间: 2018-05-01
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Lee H;Saini N;Howard EW;Parris AB;Ma Z;Zhao Q;Zhao M;Liu B;Edgerton SM;Thor AD;Yang X
• 通讯作者: Yang X