ABSTRACT: Background/Objectives: Tubo-ovarian high-grade serous carcinoma (HGSC) is a highly lethal malignancy, usually diagnosed at an advanced stage due to the lack of early symptoms and biomarkers. Contraceptive hormone use is associated with reduced risk of HGSC, but the relative contributions of natural versus synthetic progestins, and their interaction with estrogens, are poorly characterized. Methods: We evaluated the chemopreventive efficacy of a synthetic progestin medroxyprogesterone acetate (MPA), progesterone (P4), and combined 17β-estradiol-progesterone (E2+P4) in a well-characterized genetically engineered mouse model (GEMM) of oviductal HGSC based on conditional inactivation of one or both alleles of the Brca1, Trp53, Rb1, and Nf1 tumor suppressor genes (BPRN-het and BPRN-homo mice, respectively). Mice received hormones or placebo via slow-release pellets implanted subcutaneously, and after induction of tumor formation, mice were monitored for tumor development, progression, and survival. Tumor incidence was assessed histologically, and hormone effects were further explored via RNA-seq analysis of oviductal tissues. Results: MPA significantly reduced HGSC incidence and delayed tumor progression compared to placebo, P4, and P4 + E2, in both BPRN-homo and BPRN-het mice, with up to 78% tumor-free survival in the MPA-treated BPRN-het cohort. P4 monotherapy did not provide significant protection vs. placebo, while the E2+P4 combination accelerated tumorigenesis and reduced survival (p < 0.0001 in BPRN-homo and p = 0.0004 in BPRN-het mice). MPA did not affect tumorigenesis in a colon cancer GEMM, or the growth of mouse HGSC-derived cells in vivo, suggesting a role for MPA in the early stages of HGSC development. Gene expression analyses showed that P4 and MPA downregulated cholesterol homeostasis, early and late estrogen response, and epithelial-mesenchymal transition pathways, though only MPA translated this into substantial tumor protection. Conclusions: These findings demonstrate that a synthetic progestin, specifically MPA, confers robust protection against HGSC development, while P4 is not effective and a combination including E2 increases risk. This work also illustrates how HGSC GEMMs can be used to compare the chemopreventive effects of various synthetic progestins on HGSC development in order to prioritize the most effective ones for use in preventing HGSC in high-risk populations.
