# Modeling Factors Associated with Risk of High-Grade Serous Carcinoma in Mice

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $533,016

## Abstract

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 mo...

## Key facts

- **NIH application ID:** 9842617
- **Project number:** 5R01CA226756-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** KATHLEEN R. CHO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $533,016
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842617

## Citation

> US National Institutes of Health, RePORTER application 9842617, Modeling Factors Associated with Risk of High-Grade Serous Carcinoma in Mice (5R01CA226756-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9842617. Licensed CC0.

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