Abstract
Abstract Progesterone promotes proliferation and pro-survival in the breast, but inhibits growth in the reproductive tract and ovaries. Herein, using progesterone receptor (PR) isoform-specific ovarian cancer models, we show that PR-A and PR-B promote expression of distinct gene sets that differ from PR-driven genes in breast cancer cells. In ovarian cancer models, PR-A primarily regulates genes independently of progestin, while PR-B is the dominant ligand-dependent isoform. Notably, FOXO1 and the PR/FOXO1 target-gene p21 are repressed by PR-A, but induced by PR-B. In the presence of progestin, PR-B, but not PR-A, robustly induced cellular senescence via FOXO1-dependent induction of p21 and p15. ChIP assays performed on PR-isoform specific cells demonstrated that while each isoform is recruited to the same PRE-containing region of the p21 promoter in response to progestin, only PR-B elicits active chromatin. Overexpression of constitutively active FOXO1 (FOXO1-AAA) in PR-A-only expressing cells conferred robust ligand-dependent upregulation of the PR-B-target genes GZMA, IGFBP1, and p21, and induced cellular senescence. Similar results were observed when PR-A was titrated into PR-B-containing cells. PR isoform-specific regulation of the FOXO1/p21 axis recapitulated in human primary ovarian tumor explants treated with progestin. Our data indicate a key requirement for FOXO1 (a PR-B-induced, but PR-A-repressed gene) in progesterone signaling to cellular senescence in ovarian cancer cells and reveal a novel mechanism for PR-target gene (FOXO1) control of hormone sensitivity. Ultimately, harnessing PR isoform-specific gene regulation in hormone-driven cancers may provide a means to therapeutically induce the protective actions of progesterone while blocking unwanted proliferative and pro-survival effects. Citation Format: Caroline H. Diep, Todd P. Knutson, Laura J. Mauro, Carol A. Lange. FOXO1 is a key determinant of progesterone receptor isoform-specific senescence programming in ovarian cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A39.
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