Abstract B50: Direct interrogation of the incessant ovulation hypothesis in a high-fidelity mouse model of high-grade serous cancer

Abstract

Abstract The biologic basis for factors that modify risk of developing high-grade serous carcinoma remains understudied. In particular, the “Incessant Ovulation” hypothesis remains a plausible model to unify the observed risks associated with more ovulations (increasing age, early menarche/late menopause) as well as protection conferred by oral contraceptive use, multiparity, and breastfeeding. We used genetically engineered mouse models (GEMMs) of HGSC to directly interrogate the role of aging and multiparity as deleterious and protective risk factors, respectively, for HGSC development. Specifically, we utilized oviductal-restricted tamoxifen-inducible Cre recombinase to drive conditional bi-allelic inactivation of key tumor-suppressor genes (Brca1, Trp53, Rb1, Nf1) in the murine fallopian tube (oviduct). In our genetically engineered mice, autochthonous tumors arise with high penetrance in response to tamoxifen treatment, albeit with prolonged latency. As a consequence, the models allow us to evaluate effects of multiparity and aging on tumor development and progression. To test effects of multiparity, two cohorts of mice were tested, one with two floxed alleles of all 4 TSGs (BPRN), and another in which one allele of Nf1 was wild-type (BPRNfl/+). Mice were treated with tamoxifen and then continuously caged with a breeding male for a total of up to 9 pregnancies. Control mice were treated with tamoxifen and then remained nulliparous until sacrifice. The total number of pregnancies ranged from 5 to 9 for each mouse in the multiparous groups. Mice were euthanized 62 weeks post-TAM or earlier, if humane endpoints were reached. No apparent differences in diagnosis at study endpoint was observed in the multiparous BPRN versus nulliparous group (p=0.34, Mantel-Haenszel Chi-square test of association). Interestingly, the control mice showed a trend for worse diagnosis compared to the BPRNfl/+ mice at study endpoint (p=0.02). In the aging cohort, control BPRN mice were exposed to tamoxifen at 8 weeks of age and followed to humane endpoints. The experimental group was aged to 9 months, exposed to tamoxifen and then followed to humane endpoints. Survival post-TAM was observed to be shortened in the older animals (median 45.5 weeks versus 57 weeks in control mice, log rank test p=0.0033). Using Cox proportional hazard models, aging was associated with a hazard ratio of 2.8 with 95% CI of 1.4-5.9. Collectively these data suggest that multiple pregnancies alone delays HGSC development and progression in certain genetic contexts, while in contrast, tumor induction in aged mice is associated with significantly shorter survival. Together, these results help credential these GEMMs as useful tools with which to explore the biologic basis for risk factors presumed to underly the development of HGSC. Citation Format: Yali Zhai, Kevin McCool, Rork Kuick, Lixing Chen, Eric R. Fearon, Kathleen R. Cho. Direct interrogation of the incessant ovulation hypothesis in a high-fidelity mouse model of high-grade serous cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B50.