Abstract AS06: Development and characterization of an oviduct-specific model of high-grade serous carcinoma

Abstract

Abstract Recent studies suggest the most common and lethal type of “ovarian” cancer, high-grade serous carcinoma (HGSC), often arises from fallopian tube epithelium rather than the ovarian surface epithelium. Their intraperitoneal location and microscopic size make it very difficult to screen for, or study the biology of early tubal lesions in humans, as most are discovered incidentally in women with hereditary predisposition to ovarian cancer who elect prophylactic salpingo-oophorectomy for cancer risk-reduction. Although most cases of pelvic HGSC probably originate in the fallopian tube, roughly one-third lack evidence of tubal origin. These cases may arise from ectopic tubal-type epithelium (endosalpingiosis) present in the ovary, peritoneum, or at other sites. Mouse models that closely mimic the genetics and biology of human HGSCs may be useful for clarifying how tubal and non-tubal pelvic HGSCs develop and progress. We have developed transgenic (Ovgp1-iCreERT2) mice allowing conditional (tamoxifen [TAM]-inducible) expression of Cre recombinase exclusively in the oviductal epithelium, using a single transgene. Using double transgenic Ovgp1-iCreERT2;R26LSL-eYFP mice in which TAM treatment activates eYFP reporter protein expression in oviductal epithelial cells, we have shown that tubal-type inclusion glands (endosalpingiosis) expressing both eYFP and OVGP1 are present in a subset of murine ovaries following treatment with TAM. The findings suggest that oviductal epithelium can detach from the oviduct and traffic to the ovaries, where it implants through breaks in the OSE and maintains its tubal-type differentiation. Preliminary data also suggest that the frequency of ovarian endosalpingiosis increases over time and by superovulating the mice. The latter finding raises the possibility that at least some of the protective effects of high parity and oral contraceptive use on human ovarian cancer risk is related to reduced likelihood of acquiring endosalpingiosis from which “ovarian” HGSCs may eventually arise. We have further shown that Ovgp1-iCreERT2;Trp53fl/fl;Brca1fl/fl mice develop oviductal lesions identical to human serous tubal intraepithelial carcinomas (STICs) after TAM treatment and have identified additional genetic alterations that cooperate with Trp53 and Brca1 inactivation in oviductal HGSC pathogenesis in our model system. Murine models of HGSC that recapitulate their human tumor counterparts provide excellent in vivo systems with which to define the cellular and molecular events associated with HGSC development and progression. Citation Format: Yali Zhai, Rong Wu, Tom C. Hu, Eric R. Fearon, Kathleen R. Cho. Development and characterization of an oviduct-specific model of high-grade serous carcinoma [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS06.