Abstract POSTER-BIOL-1311: Mechanisms of differential activities of progesterone receptor (PR) isoforms in ovarian cancer models

Abstract

Abstract Progesterone is proliferative in the breast, but inhibitory in the reproductive tract and ovaries. Elevated circulating progesterone levels observed during pregnancy or through the use of progestin-containing oral contraceptives are associated with decreased lifetime risk of ovarian cancer (OC). In contrast, low progesterone or the functional loss of PR are associated with increased risk. The detailed mechanisms of progesterone’s protective role in OC are not well understood. The actions of progesterone are mediated through two nuclear receptors, the full-length PR-B and the N-terminally truncated PRA. While PR-A and PR-B share the same amino acid sequence downstream of the extreme N-terminus (B-upstream segment or BUS) that is missing in PR-A, they are functionally distinct transcriptional regulators. While PR-isoform specificity has been extensively studied in the breast (PR-B is required for mammary gland development and proliferative in breast cancer models), little is understood about the specific actions of PR isoforms in the ovary. It has been suggested that PR-A is primarily an inhibitory isoform that acts to suppress transcriptional actions of ER-alpha and PR-B. Further complexity is conferred by compartmentalized PR. For example, in the reproductive track, progestins may act primarily through stromal PR-A as potent antagonists of estrogen-induced epithelial hyperplasia. More recently, we have demonstrated that PRB is an OC tumor suppressor that exhibits anti-proliferative properties by inducing cellular senescence. In OC cells, in the presence of progestins, PR-B induces cellular senescence through a mechanism that involves FOXO1-dependent induction of p21 expression. In contrast to PR-B, progestin stimulation of PR-A failed to upregulate p21 and FOXO1 mRNA and thus did not induce a cellular senescence phenotype. However, we detected either PR-B or PR-A and FOXO1 within the same PRE-containing region of the p21 upstream promoter, suggesting that PR-A may actively suppress the expression of this gene, while PR-B forms an active transcriptional complex. PR isoforms differentially associate with protein kinases that in turn alter their transcriptional activity at selected target genes. We speculated that PR isoforms directly associated with FOXO1 in transcriptional complexes alter the phosphorylation state of FOXO1 to dictate the degree of isoform-specific PR target gene expression, thereby determining cell fate. Future studies will define how the PR isoforms differentially cooperate with FOXO1 as either regulated (i.e. phosphorylated) activating or repressive transcription complexes on target genes that control cell fate. Overall, identifying the mechanisms governing PRA versus PR-B specific gene regulation may provide a means to therapeutically induce the protective actions of progesterone in hormone-driven cancers towards specific cell fates (e.g. senescence relative to proliferation). (Studies supported by NIH R01 CA159712, T32 CA009138, CTSA UL1TR000114, MN Ovarian Cancer Alliance, and Doctoral Dissertation Fellowship.) Citation Format: Caroline H. Diep, Carol A. Lange. Mechanisms of differential activities of progesterone receptor (PR) isoforms in ovarian cancer models [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1311.