ORF48-08 - Investigating Progesterone Receptor-Driven Actions in Therapy-Resistant ER+ Breast Cancer

Estrogen receptor positive (ER+) breast cancer accounts for ~75% of all breast cancer cases. Endocrine therapies are the current standard of care and work by targeting ER action. While these endocrine therapies are highly effective, up to 40% of patients develop therapy resistance, leading to recurrence, metastasis, and increased mortality. ER gain-of function mutations are a mechanism of therapy resistance that result in a constitutively active ER. The most commonly occurring ER mutations, Y537S and D538G, exhibit a reduced response to current endocrine therapies. While most studies on endocrine therapy resistance focus on understanding the loss of ER response, recent evidence implicates the progesterone receptor (PR) as an independent driver of breast cancer progression. PR mediates the expansion of cancer stem cells (CSCs), a therapy-resistant subpopulation of cells in recurrent breast tumors. Our data demonstrate that PR-driven CSC populations are present in models of mutant ER+ breast cancer, but the mechanisms by which this occurs are not yet understood. Our objective is to elucidate PR-driven actions in CSCs that contribute to therapy resistance. Our preliminary RNA-sequencing data indicate that PR upregulates metabolic pathways in CSC populations in Y537S ER+ breast cancer models. Based on these findings, we hypothesize that PR facilitates metabolic reprogramming to promote CSC expansion in mutant ER+ breast cancer. To test this, we will investigate the impact of PR on metabolic pathways in mutant ER+ models using extracellular flux assays and metabolite quantification assays. Initial results suggest that PR activity increases glycolysis while reducing, or having no effect on, mitochondrial respiration, guiding our focus toward alternative metabolic processes regulated by PR. By elucidating the molecular mechanisms through which PR drives CSC expansion, this study aims to uncover novel contributors to endocrine resistance and identify potential therapeutic targets to improve outcomes for patients with metastatic ER+ breast cancer.