Abstract 2621A: Progesterone receptor-mediated repression of STAT5A-target genes implicated in breast cancer development

Recent clinical data suggest that progesterone and the progesterone receptor (PR) promote the development of breast cancer. PR itself is a transcription factor, and likely cooperates with other transcription factors to alter tumorigenesis in the mammary gland. ChIP-seq data from T47D breast cancer cells treated with R5020 (synthetic progesterone) showed that PR binding sites were enriched in signal transducers and activators of transcription 5A (STAT5A) gamma interferon activated sites (GAS), the genomic binding sites for STAT5A. This suggests possible adjacent or overlapping binding sites for STAT5A and PR. STAT5A is activated in a similar manner to PR: phosphorylation leads to dimerization and translocation to the nucleus, DNA binding and regulation of target genes involved in mammary gland development, inflammation, and proliferation. The clinical data surrounding the role for STAT5A in breast cancer risk and progression are mixed, and suggest that STAT5A activity in breast cancer is very context dependent, varying based on hormone receptor status. PR and STAT5A are both required for normal mammary gland development and, interestingly, when knocked out arrest at the same stage of mammary gland ductal branching. These data imply putative crosstalk between PR and STAT5A, perhaps through an interaction between these two transcription factors. Co-IP experiments in T47D cells showed an interaction between PR and STAT5A that is regulated by the addition of PR ligand and/or prolactin (STAT5A activator in the breast/mammary gland). To determine the implication of this interaction on STAT5A transcriptional activity we performed a luciferase assay. We transfected a STAT5A target gene (CISH) linked to a luciferase reporter into T47D cells stably expressing shRNA for PR and non-silencing (NS) control. Interestingly, when both ligands for STAT5A and PR were present there was repression of STAT5A transcription of the luciferase reporter compared to when STAT5A ligand was present alone. This repression was lost in cells expressing shRNA for PR. This PR dependent repression was verified in the context of chromatin looking at select STAT5A-target gene (CISH, EREG, and PTHrP), expression via qPCR; prolactin-activated expression of these genes was potently repressed in response to PR ligand treatment. Of note, one of the STAT5A-target genes shown to be repressed by PR, PTHrP (parathyroid hormone related protein), has been linked to breast cancer progression, and specifically, immune cell recruitment to mammary gland tumors. Studies are ongoing now to determine how PR-mediated repression of PTHrP may affect immune cell recruitment to mammary gland tumors models in mice. Understanding the crosstalk between PR and STAT5A, and what transcriptional programs are jointly regulated/repressed by these two transcription factors, could lead to the discovery of novel, PR-based therapies in breast cancer. Citation Format: Sean Holloran, Gloria Trinca, Christy Hagan. Progesterone receptor-mediated repression of STAT5A-target genes implicated in breast cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2621A.