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

在子宫内暴露于酒精会导致乳腺干细胞失调和日后患肿瘤的风险。

• 批准号: 10618844
• 负责人: XIAOHE YANG
• 金额: $ 14.98万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-10 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618844
• 关键词: Address; Alcohols; Biological Models; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Epithelial Cells; Cancer Etiology; Carcinogens; Cell Differentiation process; Cell Reprogramming; Cells; Cellular Assay; Data; Development; Diet; Dose; ERBB2 Signaling Pathway; ERBB2 gene; Environmental Risk Factor; Epithelium; Estrogen Receptor alpha; Estrogen Receptors; Etiology; Exposure to; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Development; Fetal Diseases; Future; Gene Expression; Gene Expression Microarray Analysis; Genetic Predisposition to Disease; Goals; Growth; Health; Human; ITGB3 gene; Individual; Life; Link; Liquid substance; Malignant - descriptor; Mammary Duct; Mammary Neoplasms; Mammary gland; Mammospheres; Microarray Analysis; Modeling; Molecular; Molecular Profiling; Mouse Mammary Tumor Virus; Mus; Myoepithelial; Paper; Pathway interactions; Pregnancy; Prevention strategy; Publishing; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Reporting; Risk; Role; Series; Signal Pathway; Signal Transduction; Sorting; Stem cell transplant; TNFSF11 gene; Tissues; Transforming Growth Factor beta; Transgenic Mice; Up-Regulation; Woman; alcohol consumption during pregnancy; alcohol exposure; aldehyde dehydrogenase 1; cancer prevention; cancer stem cell; career; clinically relevant; density; disorder risk; erbB-2 Receptor; estrogenic; indexing; innovation; insight; malignant breast neoplasm; mammary; maternal alcohol use; minority student; mouse model; novel; novel strategies; premalignant; prenatal exposure; promoter; research clinical testing; response; stem cell biomarkers; stem cells; stem-like cell; stemness; tissue stem cells; tumor; tumor initiation; undergraduate research experience; young adult

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.

项目概要 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 并制定预防策略。该项目的目的是研究子宫内的机制 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会对胎儿发育和以后的疾病风险产生深远的影响 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 增加患乳腺癌的风险。先前的研究还表明，子宫内暴露于酒精（IUE）之间存在联系。 酒精）和基于致癌物诱导模型的乳腺肿瘤增加。底层机制， 然而，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 酒精会显着促进 在该模型系统中，乳腺发育中雌激素的变化和肿瘤多样性的增加。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。我们还发现顶芽数量和 乳腺中的雌激素受体 (ER) 和 erbB2 信号通路因 IUE 而发生改变 酒精。在检查 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/肌上皮和管腔亚群的扩张 腺体。为了加深我们对 IUE 酒精相关乳腺癌风险的了解，我们建议进行调查 IUE 酒精诱导乳腺干细胞 (MaSC)/肿瘤起始细胞失调的机制 (TIC) 以及 MMTV-erbB2 中乳腺肿瘤发展中 ER 和 erbB2 通路之间的串扰 转基因小鼠。在我们的初步研究的支持下，我们假设 IUE 酒精可以促进乳腺发育 通过 ER-erbB2 串扰的上调和随之而来的失调来增加肿瘤风险 MaSC/祖细胞，导致癌症干细胞/TIC 扩增和肿瘤发展。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 小鼠的组织和肿瘤以及 2) 研究 IUE 酒精诱导的 ER 和 Sox2 的作用 erbB2 小鼠乳腺组织中 MaSC 和 TIC 失调的上调。临床上以此 相关的小鼠模型、重大的健康问题和新颖的方法，该项目的结果是 预计会对乳腺癌的病因学和预防产生深远的影响。