High-grade serous carcinoma (HGSC) is the most common and most lethal type of “ovarian” cancer. Most HGSCs are now believed to arise from epithelium in the distal fallopian tube, though a minority of HGSCs lack evidence of tubal origin. Population-based studies have identified several factors that are strongly associated with reduced HGSC risk, including sterilization procedures based on tubal excision, high parity, and oral contraceptive (OC) use. We do not understand how OCs and high parity protect against HGSC or how these protective effects can be maximized. Likewise, the roles of the fallopian tubes and ovaries and their cross-talk in HGSC pathogenesis remain incompletely understood. Intact ovaries could contribute to HGSC development by harboring ectopic tubal epithelium from which non-tubal HGSCs may arise, and/or by exposing the distal fallopian tube epithelium (FTE) to hormones and other factors, including those in follicular fluid released at the time of ovulation. Given the many challenges associated with detecting HGSC precursors and small tubal HGSCs before they have metastasized, and effecting cures for women with widely metastatic HGSC, an enhanced focus on preventing these tumors is warranted. Genetically engineered mouse models (GEMMs) of cancer may provide tractable and relatively rapid systems with which to test cancer prevention strategies and inform cancer prevention trials in humans. To date, no GEMMs have been credentialed for use in studying factors known to alter HGSC risk. We have developed transgenic (Ovgp1-iCreERT2) mice that allow conditional (tamoxifen [TAM]-inducible) activation of Cre recombinase exclusively in the FTE. We have also identified specific combinations of conditional tumor suppressor gene (TSG) alterations, prioritized because they are known to be frequently inactivated in human HGSCs (Brca1, Trp53, Rb1, Nf1 [BPRN] and Brca1,Trp53, Pten [BPP]), that lead to oviductal HGSCs following TAM treatment of Ovgp1-iCreERT2 mice that also carry the conditional TSG alleles. FTE from these mice can be cultured as organoids and transformed in vitro, allowing some risk factors to be tested in parallel with studies in vivo. Our new HGSC GEMMs will be employed to test the impact of factors known to be associated with human HGSC risk, with the goal of credentialing the models as genetically and biologically relevant tools with which to better understand how specific factors reduce HGSC risk, and for future use in testing novel HGSC prevention strategies. Four Aims are proposed: 1) To test whether high parity slows oviductal tumor development and/or progression in our BPRN model of HGSC; 2) To determine whether hormones of the types present in OCs alter the development and/or progression of oviductal HGSCs in BPRN mice; 3) To establish the preventive effects of bilateral risk-reducing salpingectomy (RRS) and salpingo-oophorectomy (RRSO) on the development of ovarian and/or primary peritoneal HGSC in our BPRN and BPP models; and 4) To test effects of pre-ovulatory follicular fluid on FTE in vitro and in vivo.

RELEVANCE TO PUBLIC HEALTH STATEMENT: High-grade serous carcinoma (HGSC) is the most lethal type of gynecological cancer in the United States and strategies for preventing these cancers are sorely needed. This project will test several factors known to be associated with HGSC risk in genetically engineered mouse models of HGSC, with the goal of credentialing the models as genetically and biologically relevant tools with which to test novel HGSC prevention strategies and prioritize them for trials in humans.