MON-267 - Progesterone Receptor Binding Interactions in Therapy-Resistant ER+ Breast Cancer

Estrogen receptor positive (ER+) breast cancer makes up about 75% of newly diagnosed cases, expressing estrogen and often progesterone receptors (PR). ER and PR are major drivers of ER+ breast cancer progression and can form complexes to regulate transcription of tumor promoting genes. ER+ breast cancer patients are treated with ER-targeted approaches known as endocrine therapies which are highly effective. However, a major clinical problem is that approximately 40% of these patients experience therapy resistance. Cancer stem cells (CSC) are a subpopulation of cells present in breast cancer tumors that are resistant to standard breast cancer treatments. Another mechanism that contributes to therapy resistance is ER mutations, the most common of which are point mutations Y537S and D538G, creating a ligand-independent, constitutively active ER. In our ER+ breast cancer cell models, the percentage of CSCs increase in mutant ER cells (Y537S and D538G). Our prior research indicates PR promotes the expansion of CSCs. We found that the increase in CSCs is significantly diminished in a mutant ER cell line (Y537S) when PR is knocked down, suggesting a link between PR, CSC expansion, and therapy resistance. My objective is to analyze the mechanisms by which PR promotes CSC expansion and therapy resistance while evaluating the therapeutic potential of PR. Our data shows that in the context of therapy resistance, PR becomes an independent contributor to metastatic ER+ breast cancer and functions in the absence of estrogen signaling. In conjunction, we see decreased ER/PR interactions in mutant ER cell models (Y537S and D538G) which suggests PR function may be driven by altered binding patterns. I hypothesize that PR actions are mediated by alterations in binding partners that promotes the expansion of CSCs in therapy resistant ER+ breast cancer. To understand how changes in PR binding contribute to therapy resistance, we first aim to analyze what altered PR interactions exist in therapy resistant settings. Mass spectrometry will be used to identify binding partners of PR. These studies will help identify novel PR binding partners as targetable interactions to reduce progression of resistant ER+ breast cancer.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*