Abstract 4378: Contribution of ERα/PR crosstalk to endocrine therapy resistance in breast cancer

Abstract

Abstract 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. ERα/PR crosstalk, referring to the complex relationship of ERα and progesterone receptor (PR) interaction, offers therapeutic value in targeting both nuclear receptors simultaneously in ERα/PR-positive breast cancers. Previous research identified a synergistic effect of treating ERα-WT cancer cells with ERα/PR antagonism, where combined treatment results in tumor regression in vivo and increased cell death in vitro. Conversely, preliminary data suggests that treatment of ERα-Y537S-containing tumors with combined ERα and PR antagonists results in significantly increased proliferation in vivo and reduced cell death in vitro. 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. Using a three-dimensional culture system of patient-derived xenografts grown as organoids (PDxO), I have observed a synergistic effect of certain combinations of ERα/PR antagonists in the context of ERα-WT similar to previous results in two-dimensional cell culture. At the level of transcription, PR-associated transcriptional activity appears to be significantly altered in homozygous ERα-Y537S T47D cells compared to ERα-WT cells. Further understanding the role of ERα-Y537S in altering gene expression and reducing the response to SERM and SPRM treatment will provide understanding as to why these tumors are resistant to standard-of-care treatment and will suggest alternative targets for treatment as well. Citation Format: Rosemary J. Huggins. Contribution of ERα/PR crosstalk to endocrine therapy resistance in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4378.