Developmental Exposures, Stem Cell Reprogramming, and Breast Cancer Disparties

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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.