Hormone regulation of ER+ breast cancer heterogeneity and cancer stem cells

While ER is the principal biomarker and target for breast cancer therapy, its expression varies widely between and within tumors. We are studying mechanisms that drive intratumoral heterogeneity in ER expression, leading to mixed populations of ER+ and ER− cells. The ER− cells often expand upon endocrine resistance and behave like cancer stem cells (CSC) that, compared to intratumoral ER+ cells, are more tumor initiating and drug resistant. Our current research is using single cell (sc) RNA-sequencing and Assay for Transposase-Accessible Chromatin (ATAC)-sequencing approaches in order to determine the mechanism that silences ER, PR, and a luminal gene signature, with simultaneous activation of a CSC gene signature in breast cancer cells. The goal is to identify transcription factors that orchestrate this phenotypic switch and to eventually eliminate the ER− subpopulations to prevent tumor progression and improve response to endocrine therapies.