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 theBrca1,Trp53,Rb1, andNf1tumor suppressor genes (BPRN-het andBPRN-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 bothBPRN-homo andBPRN-het mice, with up to 78% tumor-free survival in the MPA-treatedBPRN-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 inBPRN-homo andp= 0.0004 inBPRN-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.
背景/目的：输卵管-卵巢高级别浆液性癌（HGSC）是一种高致死性恶性肿瘤，由于缺乏早期症状和生物标志物，通常在晚期才被诊断。避孕激素的使用与降低HGSC风险相关，但天然孕激素与合成孕激素的相对贡献及其与雌激素的相互作用尚不清楚。方法：我们在一个特征明确的输卵管HGSC基因工程小鼠模型（GEMM）中评估了合成孕激素醋酸甲羟孕酮（MPA）、孕酮（P4）以及17β-雌二醇联合孕酮（E2 + P4）的化学预防效果。该模型基于条件性失活一个或两个等位基因的Brca1、Trp53、Rb1和Nf1肿瘤抑制基因（分别为BPRN-het和BPRN-homo小鼠）。小鼠通过皮下植入缓释颗粒接受激素或安慰剂。诱导肿瘤形成后，监测小鼠的肿瘤发生、进展和生存情况。通过组织学评估肿瘤发生率，并通过输卵管组织的RNA-seq分析进一步探讨激素效应。结果：与安慰剂、P4以及P4 + E2相比，MPA在BPRN-homo和BPRN-het小鼠中均显著降低了HGSC发生率并延缓了肿瘤进展，其中MPA处理的BPRN-het组无瘤生存率高达78%。P4单药治疗相比安慰剂未提供显著保护，但P4的效果可能受到未能实现4-8周后持续释放的影响。E2 + P4联合用药加速了肿瘤发生并降低了生存率（BPRN-homo小鼠p < 0.0001，BPRN-het小鼠p = 0.0004）。MPA在结肠癌GEMM中不影响肿瘤发生，也不影响小鼠HGSC来源细胞的体内生长，表明MPA在HGSC发展的早期阶段发挥作用。基因表达分析显示，P4和MPA下调了胆固醇稳态、早期和晚期雌激素反应以及上皮-间质转化通路，但只有MPA提供了肿瘤保护。结论：这些发现表明，合成孕激素（特别是MPA）对HGSC发展具有强大的保护作用，而包含E2的联合用药（E2 + P4）则会增加风险。这项工作还说明了如何利用HGSC GEMM比较各种合成孕激素对HGSC发展的化学预防效果，以便优先选择最有效的药物用于普通人群和高危人群的HGSC预防。
肿瘤(癌症)患者之家