Medroxyprogesterone Acetate Inhibits Tumorigenesis in Mouse Models of Oviductal High-Grade Serous Carcinoma

TL;DR

Medroxyprogesterone acetate (MPA) significantly reduces the risk of high-grade serous ovarian cancer in mice, while combining it with estrogen increases cancer risk.

Contribution

The study identifies MPA as a potent chemo-preventive agent for HGSC and demonstrates that estrogen-progestin combinations may be harmful.

Findings

MPA significantly inhibits tumor development and prolongs survival in mouse models of HGSC.

Estradiol combined with progesterone accelerates tumorigenesis and shortens survival in mice.

MPA's protective effects are specific to early stages of HGSC and not observed in colon cancer models.

Abstract

Oral contraceptive use is known to significantly reduce the risk of developing the most common and lethal type of ovarian cancer, known as high-grade serous carcinoma (HGSC). The risk reduction is likely attributable to synthetic progestins in oral contraceptives, but it is not known which of the many types of progestins are most effective, and whether combination with estrogen mitigates their protective effects. We used genetically engineered mouse models of tubo-ovarian HGSC to show that medroxyprogesterone acetate (MPA), a common constituent of contraceptive hormones, significantly inhibits tumor development and prolongs survival. In contrast, estradiol in combination with progesterone accelerates tumorigenesis and significantly shortens survival. The findings provide strong support for MPA as a chemo-preventive agent for HGSC, confirming observations based on large-scale retrospective studies in humans. The model system offers a platform for testing other progestins and dosing strategies to identify the most effective ones in preventing HGSC in high-risk populations.

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 a reduced risk of HGSC, but the relative contributions of natural versus synthetic progestins, and their interaction with estrogens, are poorly understood. Methods: We evaluated the chemo-preventive 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 the 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. After induction of tumor formation, the 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 the 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. the placebo, but the effects of P4 could have been impacted by a failure to achieve sustained release of the hormone beyond 4–8 weeks. 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 the role of 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 afforded tumor protection. Conclusions: These findings demonstrate that a synthetic progestin, specifically MPA, confers robust protection against HGSC development, while a combination including E2 (E2 + P4) increases risk. This work also illustrates how HGSC GEMMs can be used to compare the chemo-preventive effects of various synthetic progestins on HGSC development in order to prioritize the most effective ones for use in preventing HGSC in both general and high-risk populations.

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