In utero exposure to alcohol-induced mammary stem cell deregulation and tumor risk later in life.

项目总结 我们的长期目标是了解宫内酒精暴露在乳腺癌病因学中的机制。 并制定预防策略。本项目的目的是研究子宫内排卵的机制。 暴露在酒精诱导的乳腺肿瘤发展中，重点是干细胞的去调节。 怀孕期间母亲饮酒对胎儿发育和以后的疾病风险有深远的影响 生活。越来越多的证据表明，在子宫内暴露于某些环境因素与 放大了患乳腺癌的风险。以前的研究也表明，宫内酒精暴露(IUE)与 酒精)和基于致癌物诱导模型的乳腺肿瘤增加。潜在的机制， 然而，目前仍不清楚。我们将使用MMTV研究IUE酒精对乳腺肿瘤风险的影响- ERBB2转基因小鼠模型。我们的初步数据表明，IUE酒精诱导显著促进 在这个模型系统中，乳腺发育中的雌激素变化和增加的肿瘤多样性。微阵列 分析表明，IUE酒精诱导与受体酪氨酸激酶相关的独特基因表达 癌前病变组织中的信号通路。我们还发现，顶端花蕾数量和 雌激素受体(ER)和erbB2信号通路对IUE的反应在乳腺中发生改变 酒精。在检测IUE酒精对乳腺上皮细胞分化的影响后，我们发现IUE 酒精诱导青春期乳腺基底/肌上皮亚群和管腔亚群的扩张 腺体。为了促进我们对IUE酒精相关乳腺癌风险的理解，我们建议调查 IUE酒精诱导的乳腺干细胞/肿瘤起始细胞失控的机制 乳腺癌MMTV-erbB2中ER和erbB2信号通路的抽动和串扰 转基因小鼠。在我们的初步研究的支持下，我们假设酒精促进乳房 ER-erbB2串扰上调和随之而来的放松对 MASCS/祖细胞，导致癌症干细胞/TIC的扩张和肿瘤的发展。具体的 目的是：1)确定IUE酒精对乳腺MASC和TIC扩张和功能的影响 MMTV-erbB2小鼠的组织和肿瘤；2)研究IUE酒精诱导的ER和Sox2的作用 小鼠乳腺组织中MASCS和TICS基因表达上调。在临床上有这种情况 相关的小鼠模型，重大的健康问题，以及新的方法，该项目的结果是 预计将对乳腺癌的病因和预防产生深远的影响。

PROJECT SUMMARY Our long-term goal is to understand the mechanisms of in utero exposure to alcohol in breast cancer etiology and develop preventative strategies. The objective of this project is to investigate the mechanisms of in utero exposure to alcohol-induced mammary tumor development with a focus on stem cell deregulation. Maternal alcohol use during pregnancy has a profound impact on fetal development and disease risk later in life. Increasing evidence indicates that in utero exposure to certain environmental factors is associated with amplified breast cancer risk. Previous studies also suggest a link between in utero exposure to alcohol (IUE alcohol) and increased mammary tumors based on carcinogen-induced models. The underlying mechanisms, however, remain unclear. We will study the effects of IUE alcohol on mammary tumor risk using the MMTV- erbB2 transgenic mouse model. Our preliminary data demonstrated that IUE alcohol induces significant pro- estrogenic changes in mammary development and increased tumor multiplicity in this model system. Microarray analysis showed that IUE alcohol induces distinctive gene expression associated with receptor tyrosine kinase signaling pathways in the premalignant mammary tissues. We also found that terminal end bud numbers and estrogen receptor (ER) and erbB2 pathway signaling were modified in the mammary glands in response to IUE alcohol. Upon examining the effects of IUE alcohol on mammary epithelial cell differentiation, we found that IUE alcohol induced the expansion of the basal/myoepithelial and luminal subpopulations in pubertal mammary glands. To advance our understanding of IUE alcohol-associated breast cancer risk, we propose to investigate the mechanisms of IUE alcohol-induced deregulation of mammary stem cells (MaSCs)/tumor-initiating cells (TICs) and crosstalk between ER and erbB2 pathways in mammary tumor development in MMTV-erbB2 transgenic mice. Supported by our preliminary studies, we hypothesize that IUE alcohol promotes mammary tumor risk through the upregulation of ER-erbB2 crosstalk and the consequent deregulation of MaSCs/progenitor cells, which leads to cancer stem cell/TIC expansion and tumor development. The specific aims are: 1) To determine the effects of IUE alcohol on MaSC and TIC expansion and function in mammary tissues and tumors from MMTV-erbB2 mice and 2) To investigate the role of IUE alcohol-induced ER and Sox2 upregulation in the deregulation of MaSCs and TICs in mammary tissues from erbB2 mice. With this clinically relevant mouse model, significant health concern, and novel approaches, the results from this project are expected to have a profound impact on breast cancer etiology and prevention.