Abstract 4050: Progesterone receptor signaling induces cellular senescence in ovarian cancer cells.

Abstract Despite major advancements in surgical techniques and chemotherapeutics, over 90% of women with advanced ovarian cancer die with recurrent disease, due to the emergence of chemo-resistant tumors (Bukowski et al 2007). In recent years, the progesterone receptor (PR) has become an attractive target in ovarian cancer. PR is typically expressed in normal ovarian surface epithelial (OSE) cells, but the detection of PR mRNA and protein decreases during the transformation to malignancy. However, up to 35% of ovarian tumors express abundant PR. Several independent studies have indicated that the expression of PR in ovarian tumors is associated with longer progression-free survival in ovarian cancer patients (Hempling et al 1998, Munstedt et al 2000, Sinn et al 2011). The detailed molecular mechanisms of PR expression in OSE cells and its anti-tumorigenic effects remain poorly understood. To study the suppressive role of PR in ovarian cancer in the absence of added estrogen (i.e. needed to stimulate PR expression), we created ES-2 ovarian cancer cells stably expressing vector control or GFP-tagged PR-B. Unmodified ER+/PR+ PEO4 ovarian cancer cells were included to validate our findings. Progestin stimulation (R5020; 10 nM) of ES-2 cells stably expressing GFP-PR inhibited the formation of large colonies in soft-agar assays, but yielded a significant increase in the number of viable, very small colonies relative to vehicle-treated and PR-null cohorts. Continuous treatment with R5020 induced cellular senescence characterized by altered cellular morphology, senescence-associated β-galactosidase activity, irreversible G1 cell-cycle arrest, and upregulation of the cell-cycle inhibitor, p21, as well as the Forkhead-box transcription factor, FOXO1. Notably, both PR-B and FOXO1 were detected within the same PRE-containing regions of the p21 upstream promoter. Stable knock-down using lentiviral shRNAs targeting FOXO1 inhibited progestin-induced p21 expression and blocked the development of senescence, suggesting that progestin-induced cellular senescence in PR+ ovarian cancer cells is mediated by FOXO1-dependent p21 expression. Overall, these findings support the concept of PR as a tumor suppressor in ovarian cancer cells that exhibits its inhibitory effects by inducing cellular senescence. Clinical targeting of the PR-FOXO1-p21 signaling pathway may provide a useful strategy to induce irreversible cell cycle arrest and sensitize ovarian cancer cells to existing chemotherapies as part of combination therapy. (This work was supported by grants from the Minnesota Ovarian Cancer Alliance (MOCA), the Cancer Biology Training Grant (NIH T32 CA009138), and the University of Minnesota Clinical and Translational Science Institute (CTSI) F&T Pilot Grant.) Citation Format: Caroline H. Diep, Nathan J. Charles, C. Blake Gilks, Steve E. Kalloger, Peter A. Argenta, Carol A. Lange. Progesterone receptor signaling induces cellular senescence in ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4050. doi:10.1158/1538-7445.AM2013-4050