Half of estrogen receptor (ERα)-positive breast cancer patients treated with endocrine therapies display intrinsic or acquired therapy resistance. One-third of patients with acquired resistance present with metastatic tumors containing ERα-Y537S mutations. This mutation results in constitutive activity of ERα and altered ERα-associated gene expression. Previous research suggests that ERα and the progesterone receptor (PR) engage in complex interactions involving reciprocal regulation of ERα and PR transcription factor activity known as ERα/PR crosstalk. My central hypothesis is that ERα-Y537S alters the transcription factor activity of ERα and PR, causing dysregulation of gene expression in SERM-resistant breast cancer. While previous research has assessed the impact of the ERα-Y537S mutation on ERα-associated chromatin binding and gene expression, here I assess the effect of the resistance-associated ERα-Y537S mutation on ERα and PR activity and crosstalk. Simultaneous analysis of transcription factor binding activity (ChIP-seq), gene expression (RNA-seq), and proximity-based interaction (NanoBRET) indicates that active PR binding across the genome is increased in the context of ERα-Y537S, suggesting that ERα/PR crosstalk is significantly altered. Importantly, PR chromatin binding in the context of ERα-Y537S appears to be elevated regardless of the stimulation of PR activity with the agonist R5020. These findings, along with identification of candidate genes of potential therapeutic value, will be applied using patient-derived tumor organoids to determine the efficacy of simultaneously targeting ERα and PR to overcome endocrine therapy resistance in breast cancer.
Citation Format: Rosemary J. Huggins. Altered ER and PR transcription factor activity associated with endocrine therapy resistance in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 743.