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

项目摘要 我们的长期目标是了解子宫内酒精暴露在乳腺癌病因中的机制 制定预防策略。本项目的目的是研究子宫内 暴露于酒精诱导的乳腺肿瘤发展，重点是干细胞失调。 母亲在怀孕期间饮酒对胎儿发育和以后的疾病风险有着深远的影响。 生活越来越多的证据表明，子宫内暴露于某些环境因素与 乳腺癌风险增加。先前的研究也表明，子宫内酒精暴露（IUE） 酒精）和增加的乳腺肿瘤。潜在的机制， 但仍不清楚。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酒精诱导显着的前- 乳腺发育中的雌激素变化和该模型系统中肿瘤多样性的增加。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， 癌前乳腺组织中的信号通路。我们还发现，终端芽的数量和 乳腺雌激素受体（ER）和erbB 2通路信号转导在IUE反应中被改变 酒精在研究IUE酒精对乳腺上皮细胞分化的影响时，我们发现IUE 酒精诱导青春期乳腺基底/肌上皮和管腔亚群的扩增 腺体为了加深我们对IUE酒精相关乳腺癌风险的理解，我们建议调查 IUE酒精诱导乳腺干细胞/肿瘤起始细胞失调的机制 MMTV-erbB2中乳腺肿瘤发展中ER和erbB2通路之间的相互作用 转基因小鼠在我们的初步研究的支持下，我们假设IUE酒精促进乳腺癌， 通过ER-erbB2串扰的上调和随之而来的ER-erbB2串扰的失调， MaSC/祖细胞，其导致癌症干细胞/TIC扩增和肿瘤发展。具体 目的：1）研究IUE乙醇对乳腺癌组织中MaSC和TIC的扩增及功能的影响 2）研究IUE酒精诱导ER和Sox 2的作用 在来自erbB2小鼠的乳腺组织中MaSC和TIC的失调中的上调。在临床上， 相关的小鼠模型，重大的健康问题，和新的方法，该项目的结果是 有望对乳腺癌病因学和预防产生深远影响。

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.