Developmental Exposures, Stem Cell Reprogramming, and Breast Cancer Disparties

摘要 该项目的总体目标是确定乳腺干细胞和环境之间的相互作用 压力驱动三阴性乳腺癌（TNBC）种族差异的生物学基础。TNBC 非洲裔美国妇女的发病率比欧洲裔美国人高2 - 3倍。生物 造成这种显著差异的机制尚不清楚。我们的初步数据表明 广泛的种族差异暴露于多种环境毒物，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， 子宫内或青春期和怀孕期间，不成比例地增加乳腺癌的风险。暴露于 易感性窗口可以通过增加干细胞数量、改变干细胞 表观遗传重编程，或通过其他方式改变干细胞生物学。使用单细胞RNA表达 通过分析，我们发现了一种罕见的乳腺干细胞群， 在一些实施方案中，该细胞具有类似于TNBC的特征和RNA表达模式。哪些因素调节这些细胞，包括 人种/种族或环境暴露的影响未知。本建议的目的是 剖析干细胞和环境在TNBC种族差异生物学中的作用。我们将 实验挑战从流行病学上充分表征的分离的正常人乳腺干细胞 由于种族接触差异，离体接触典型毒物和毒物的妇女优先考虑。我们 中心假设是正常干细胞生物学的差异，归因于遗传或环境 这些因素（或基因-环境相互作用）是TNBC差异的基础。我们将用三个来检验这个假设 具体目的：（1）检测非裔美国人和欧洲人正常乳腺干细胞生物学的差异 通过单细胞RNA测序、三维离体培养和表观基因组分析， (2)确定非洲裔美国人和欧洲人在环境毒物暴露方面的差异 美国妇女在全国代表性数据集。(3)环境差异效应试验 有毒物质对非洲裔美国人和欧洲裔美国人乳腺干细胞的影响。这项跨学科研究将使用 将基本乳腺干细胞生物学与暴露评估相结合的最新技术， 环境流行病学和毒理学。我们希望这项研究的结果将提供重要的 通过确定造成三年前三 为精确预防乳腺癌提供可操作的目标。

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.