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: 10412484
• 负责人: XIAOHE YANG
• 金额: $ 14.9万
• 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/10412484
• 关键词: Address; Alcohols; Biological Models; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Epithelial Cells; Cancer Etiology; Carcinogens; Cell Differentiation process; Cells; Cellular Assay; Centers for Disease Control and Prevention (U.S.); Data; Development; Diet; Dose; ERBB2 Signaling Pathway; ERBB2 gene; Environmental Risk Factor; Epithelial; 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; Lead; 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; S-Phase Fraction; Series; Signal Pathway; Signal Transduction; Stem cell transplant; TNFSF11 gene; Tissues; Transforming Growth Factor beta; Transgenic Mice; Tumor Stem Cells; Up-Regulation; Woman; alcohol consumption during pregnancy; alcohol exposure; aldehyde dehydrogenase 1; base; cancer prevention; cancer stem cell; career; clinically relevant; density; disorder risk; erbB-2 Receptor; estrogenic; 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; 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.

项目摘要 我们的长期目标是了解乳腺癌病因中的子宫内酒精暴露的机制 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育，重点是干细胞放松管制。 怀孕期间的孕产妇使用饮酒对胎儿发育和疾病风险产生深远影响 生活。越来越多的证据表明，在子宫内暴露于某些环境因素中 放大的乳腺癌风险。先前的研究还表明，在子宫内暴露于酒精中的联系（iue） 基于致癌物诱导的模型，酒精）并增加了乳腺肿瘤。基本机制， 但是，尚不清楚。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酒精会引起大量的促进 在该模型系统中，乳腺发育的雌激素变化和肿瘤多样性增加。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 乳腺组织前乳腺组织中的信号通路。我们还发现终端末端数字和 雌激素受体（ER）和ERBB2途径信号转导在乳腺中响应于IUE 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 酒精诱导了青春期乳腺中基底/肌上皮和腔内亚植物的扩张 腺体。为了促进我们对与酒精相关的乳腺癌风险的理解，我们建议调查 IUE酒精引起的乳腺干细胞（MASCS）/肿瘤发射细胞的管制机制 MMTV-ERBB2的乳腺肿瘤发育中ER和ERBB2途径之间的（TICS）和串扰 转基因小鼠。在我们的初步研究的支持下，我们假设iue饮酒会促进乳房 肿瘤风险通过上调ER-ERBB2串扰以及随之而来的放松管制 MASC/祖细胞，导致癌症干细胞/抽动膨胀和肿瘤发育。具体 目的是：1）确定IUE酒精对MASC和TIC扩张和功能对乳腺的影响 来自MMTV-ERBB2小鼠的组织和肿瘤，2）研究IUE醇诱导的ER和SOX2的作用 来自ERBB2小鼠的乳腺组织中的MASC和TICS失语的上调。在临床上 相关的鼠标模型，重要的健康问题和新方法，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。