Abstract 4752: Targeting senescence-induced pro-survival pathways in PR+ ovarian cancer cells

Abstract

Abstract Despite major advances in surgical techniques and chemotherapeutics, over 90% of women with advanced ovarian cancer ultimately succumb to recurrent chemo-resistant disease. Accordingly, the discovery of molecular targets that appropriate multiple signaling pathways is desperately needed. In recent years, the progesterone receptor (PR) has become an attractive target in ovarian cancer. Like estrogen receptors (ER), expression of PR in ovarian tumors is associated with longer progression-free survival of ovarian cancer patients. Both steroid hormone receptors are typically expressed in normal ovarian surface epithelial (OSE) cells, but PR mRNA and protein levels decrease during the transformation to malignancy. However, up to 35% of ovarian cancers (primarily endometrioid and serous sub-types) express abundant PR. The detailed molecular mechanisms of loss of PR expression in OSE cells and its anti-tumorigenic effects remain poorly understood. Recently, we demonstrated that PR-B is an ovarian cancer tumor suppressor that exhibits anti-proliferative properties by inducing cellular senescence. Progesterone and progestins induce FOXO1-dependent p21 expression. We showed that PR-B and FOXO1 were co-recruited to the same PRE-containing region of the p21 upstream promoter upon progestin (R5020) treatment. Both proteins were required to cooperatively induce p21 mRNA and protein expression as determined using PR-null control cells and lentiviral-delivered shRNA FOXO1-knockdown studies. Stable knock-down of FOXO1 inhibited progestin-induced p21 expression in ES-2 cells stably expressing GPF-tagged PR-B and blocked progestin-induced cellular senescence. Senescent cells, although growth arrested, remain viable and metabolically active for an extended period of time. To sustain long-term viability, senescent cells are “oncogene addicted” to intrinsically activated pro-survival pathways. For example, the epidermal growth factor (EGF) and hepatocyte growth factor (MET) receptors are constitutively active in ovarian cancer cells. Interestingly, treatment of PR+ ovarian cancer cells with small molecule inhibitors to either receptor in combination with progestin caused a dramatic increase in cell death relative to either kinase inhibitor alone. These findings, although preliminary, suggest a means to dramatically improve the sensitivity of PR+ ovarian cancer cells to apoptosis-inducing chemotherapeutic agents. Future studies will validate the biological effects of combination treatments of progestin and receptor-specific inhibitors in novel ex vivo ex-plant models, wherein primary ovarian tumors are supported by hemostatic gelatin sponges. Combination therapies that exploit mechanisms of cellular senescence may provide a novel strategy to improve current cancer therapy for patients with PR+ ovarian cancer. (Studies supported by NIH R01 CA159712, T32 CA009138, CTSA 8UL1TR000114-03, and MN Ovarian Cancer Alliance.) Citation Format: Caroline H. Diep, Carol A. Lange. Targeting senescence-induced pro-survival pathways in PR+ ovarian cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4752. doi:10.1158/1538-7445.AM2014-4752