Developmental Exposures, Stem Cell Reprogramming, and Breast Cancer Disparties

发育暴露、干细胞重编程和乳腺癌差异

• 批准号: 10548669
• 负责人: Justin Adam Colacino
• 金额: $ 3.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548669
• 关键词: 3-Dimensional; Advocate; African; African American; American; Area; Biological; Biology; Breast; Breast Cancer Patient; Breast Cancer Prevention; Breast Cancer Risk Factor; Cancer Etiology; Carcinogen exposure; Cells; Cellular biology; Characteristics; Chemicals; Complex; Data; Data Set; Development; Environment; Environmental Epidemiology; Environmental Exposure; Environmental Risk Factor; Epidemiology; Epigenetic Process; Epithelial; Ethnic Origin; European; Exposure to; Expression Profiling; Gene Expression Profile; Genetic; Genetic Transcription; Goals; Growth; Heterogeneity; Human; Hybrids; Incidence; Interdisciplinary Study; Knowledge; Life; Link; Mammary gland; Mesenchymal; Methods; Outcome; Parabens; Pattern; Predisposition; Pregnancy; Prevention strategy; Puberty; Race; Risk; Role; Techniques; Testing; Time; Tissues; Toxic Environmental Substances; Toxicant exposure; Toxicology; Woman; Work; aggressive breast cancer; base; breast stem cell; cancer health disparity; cancer prevention; cancer risk; disparity elimination; environmental chemical; environmental stressor; epigenomics; exposure route; gene environment interaction; in utero; individualized prevention; malignant breast neoplasm; mammary; metropolitan; mortality; personal care products; phthalates; prenatal exposure; racial disparity; single-cell RNA sequencing; stem; stem cell biology; stem cell function; stem cell population; stem cells; stem-like cell; targeted treatment; tissue culture; toxicant; triple-negative invasive breast carcinoma

ABSTRACT The overall goal of this project is to define how interactions between breast stem cells and environmental stressors drive the biological basis of racial disparities in triple negative breast cancers (TNBCs). TNBC incidence in African American women is two to three-fold higher than in European Americans. The biological mechanisms underlying this striking disparity are not well understood. Our preliminary data identifies widespread racial disparities in exposure to a multitude of environmental toxicants including phthalates and parabens. The breast cancer windows of susceptibility hypothesis states that environmental exposures in utero, or during puberty and pregnancy, disproportionately increase breast cancer risk. Exposures during windows of susceptibility could modify risk by the increasing the number of stem cells, altering stem cell epigenetic reprogramming, or by otherwise changing stem cell biology. Using single cell RNA expression profiling, we have identified a rare breast stem cell population with hybrid epithelial/mesenchymal characteristics and an RNA expression pattern resembling TNBCs. What factors regulate these cells, including the influence of race/ethnicity or environmental exposures, are unknown. The objective of this proposal to dissect the role of stem cells and the environment in the biology of TNBC racial disparities. We will experimentally challenge normal human breast stem cells isolated from epidemiologically well characterized women ex vivo with prototypical toxicants and toxicants prioritized because of racial exposure disparities. Our central hypothesis is that differences in normal stem cell biology, attributable to either genetic or environmental factors (or a gene-environment interaction), underlie TNBC disparities. We will test this hypothesis with three Specific Aims: (1) Test for differences in normal breast stem cell biology in African American and European American women by single cell RNA sequencing, three-dimensional ex vivo culture, and epigenomic profiling. (2) Define the disparities in exposure to environmental toxicants between African American and European American women in a nationally representative dataset. (3) Test for differential effects of environmental toxicants on African American and European American breast stem cells. This interdisciplinary study will use state-of-the-art techniques which integrate basic breast stem cell biology with exposure assessment, environmental epidemiology, and toxicology. We expect that the findings from this study will provide significant impact for reduction of TNBC incidence and mortality by defining the factors that cause TNBC disparities, providing actionable targets for precision breast cancer prevention.

摘要 这个项目的总体目标是定义乳腺干细胞和环境之间的相互作用 应激源驱动了三阴性乳腺癌(TNBCs)种族差异的生物学基础。TNBC 非洲裔美国女性的发病率是欧洲裔美国女性的两到三倍。生物学的 这种显著差异背后的机制还没有得到很好的理解。我们的初步数据显示 接触多种环境毒物，包括邻苯二甲酸盐和 对羟基苯甲酸酯。乳腺癌易感性窗口假说指出，环境暴露于 子宫，或在青春期和怀孕期间，不成比例地增加乳腺癌的风险。过程中的暴露 易感窗口可以通过增加干细胞的数量来改变风险，改变干细胞 表观遗传重新编程，或通过其他方式改变干细胞生物学。使用单细胞RNA表达 侧写：我们发现了一个罕见的上皮/间充质混合型乳腺干细胞群 特征和类似于TNBCs的RNA表达模式。是什么因素调节这些细胞，包括 种族/族裔或环境暴露的影响是未知的。这项提议的目标是 剖析干细胞和环境在TNBC种族差异生物学中的作用。我们会 实验挑战从流行病学特征良好的人乳腺中分离出的正常人类乳腺干细胞 由于种族暴露差异，使用典型毒物和毒物的体外妇女优先考虑。我们的 中心假设是正常干细胞生物学上的差异，可归因于遗传或环境 因素(或基因-环境相互作用)是TNBC差异的基础。我们将用三个例子来检验这一假设 具体目标：(1)测试非裔美国人和欧洲人正常乳腺干细胞生物学的差异 美国妇女通过单细胞RNA测序、三维体外培养和表观基因组图谱。 (2)界定非裔美国人和欧洲人在接触环境毒物方面的差异 美国女性在一个具有全国代表性的数据集中。(3)环境差异效应检验 非裔美国人和欧洲裔美国人乳房干细胞上的毒物。这项跨学科研究将使用 将基础乳腺干细胞生物学与暴露评估相结合的最先进技术， 环境流行病学和毒理学。我们预计，这项研究的结果将提供重要的 通过确定造成TNBC差异的因素对降低TNBC发病率和死亡率的影响， 为乳腺癌的精准预防提供可操作的靶点。