Objectives The purpose of this study is elucidating the role of ovarian hormones in the development of ovarian cancer.

Methods To evaluate the effects of steroid hormones on HGSC development, upon ovariectomy at 5–6 weeks of age, DKO mice were implanted subcutaneously with a pellet of 17-β estradiol (E2) (0.72 mg/90days/mouse), progesterone (P4) (25 mg/90 days/mouse), or combined E2 (0.72 mg) & P4 (25 mg). Also, for shorter periods of P4 exposure, ovariectomized DKO mice were treated with a P4 pellet of 2 mg (1 week) or 6 mg (3 weeks). Another set of ovariectomized DKO mice implanted with a placebo served as controls. To examine whether mifepristone (RU486) inhibits HGSC development in DKO mice by blocking PR, DKO mice with intact ovaries were implanted with a mifepristone pellet once at 9 mg/90 days (3 months) or three times at 33.3 mg/60 days. For a control group, DKO mice received a placebo pellet for mifepristone.

Results We show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high- grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (~18 human years).

Conclusions Targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene.