Abstract IA6: Murine models of nonserous ovarian cancer: Effects of mutant Trp53, Pik3ca, and Arida1a in a model of endometrioid carcinoma based on Wnt and PI3K/Akt pathway defects

Abstract

Abstract A dualistic pathway model of ovarian carcinoma (OvCA) pathogenesis has been proposed in which type I OvCAs are low grade, genetically stable, and relatively more indolent than type II OvCAs, most of which are high-grade serous carcinomas. Endometrioid OvCA (EOC) is a prototypical type I tumor, often harboring mutations that affect the Wnt and phosphatidylinositol 3-kinase/AKT/mTOR signaling pathways. Molecular and histopathologic analyses indicate type I and II OvCAs share overlapping features, and a subset of EOCs may undergo type I→type II progression accompanied by acquisition of somatic TP53 or PIK3CA mutations. We used a murine model of EOC initiated by conditional inactivation of the Apc and Pten tumor suppressor genes to investigate mutant Trp53 or Pik3ca alleles as key drivers of type I→type II OvCA progression. In the mouse EOC model, the presence of somatic Trp53 or Pik3ca mutations resulted in shortened survival and more widespread metastasis. In contrast, bi-allelic inactivation of Arid1a in addition to Apc and Pten actually prolonged survival and tumors with Arid1a inactivation showed more epithelial differentiation than their counterparts with intact Arid1a alleles. Our findings indicate that the adverse prognosis associated with TP53 and PIK3CA mutations in human cancers can be functionally replicated in mouse models of type I→type II OvCA progression. Moreover, the models should represent a robust platform for assessment of the contributions of Trp53, Pik3ca, and Arid1a mutations to the response of EOCs to conventional and targeted drugs. Citation Format: Kathleen R. Cho, Rong Wu, Yali Zhai, Isao Sakaguchi. Murine models of nonserous ovarian cancer: Effects of mutant Trp53, Pik3ca, and Arida1a in a model of endometrioid carcinoma based on Wnt and PI3K/Akt pathway defects. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA6.