Single-cell Assessment of Breast Cells from Genetically Diverse Individuals: A Model for Precision Toxicology to Evaluate Racial Disparities in Breast Cancer [article]

Tsu Wei Tasha Gloria Thong, University, My
2022
Breast cancer is the most diagnosed cancer and the leading cause of cancer death among women worldwide. In the US, women of African ancestry have significantly worse cancer outcomes at every age group, yet the biological basis underlying this disparity is unknown. African American communities in the US are disproportionately exposed to environmental toxicants. Of these, Bisphenol-A (BPA) and its analogues are of interest due to their ability to alter mammary gland morphogenesis and stemness in
more » ... ivo and in vitro. Together, these disparities highlight the need for better methods of precision toxicology to model environmental carcinogenesis of mammary cells from genetically diverse women. Specific Aims: The goal of this dissertation was to characterize differences in normal breast stem cell biology between women of African (AA) and European (EA) ancestry and assess the effect of environmental stressors on normal breast stem cells to provide insight into mechanisms driving racial disparities in breast cancer through the following aims 1) Establish normal mammary cell cultures in the stem cell enriching conditional reprogramming (CR) culture and characterize its effects using single cell RNA-sequencing (scRNA-seq) 2) Quantify transcriptomic, epigenomic, and genotypic differences between normal mammary stem cells from AA and EA women grown in CR culture using scRNA-seq, DNA methylation analysis, and SNP genotyping 3) Quantify transcriptomic effects of bisphenol toxicant exposure on normal mammary stem cells from genetically diverse women using scRNA-seq. Results: Results from Aim 1 indicate that the CR culture retains the epithelial cell lineages of the breast, luminal and myoepithelial, as well as inter-individual heterogeneity in gene expression. Additionally, CR mammary cells differentially express breast cancer and stem cell associated genes, exhibit a more developmentally immature transcriptomic phenotype, and promote the emergence of a unique hybrid stem cell population following reprogramming. In Aim [...]
doi:10.7302/5909 fatcat:d643vdz7tzfzzbjeeq5wumyh6m