Abstract 3289: Tissue specific expression of the PI 3-kinase mutation Pik3caH1047R induces hyperplasia and tumorigenesis in a mouse model

Abstract

Abstract Mutations in the p110α subunit of phosphoinositide 3-kinase (PI3K) (encoded by the gene PIK3CA) are frequent in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis in vivo, we generated a conditional (Cre recombinase-inducible) knock-in mouse model of the common activating mutation, Pik3caH1047R, expressed from the endogenous locus. We have then targeted the mutation to specific tissues by crossing our mouse to mice expressing Cre under the control of tissue-specific promoters. The mouse mammary gland was targeted using a transgenic mouse expressing Cre under the control of the mouse mammary tumor virus promoter (MMTV-Cre). To target the gastrointestinal tract, we used the A33CrePR2 mouse, expressing Ru486-inducible version of Cre under the control of the gpa33 promoter. Tumors were formed in both these models but only following a long latency (>15 months) suggesting that a ‘second-hit’ may be necessary for tumor development. Similarly, activation of this mutation in the mouse ovary, by injection of an adenovirus expressing Cre into the ovarian bursa, revealed that Pik3caH1047R alone is a weak activator of AKT capable of inducing premalignant hyperplasia in ovarian surface epithelium. Interestingly, we found that combining Pik3caH1047R mutation with deletion of Pten in the mouse ovary resulted in robust epithelial AKT signaling and progression to ovarian serous adenocarcinomas and granulosa cell tumors within 6 months. Therapeutic inhibition of PI3K/mTOR in these mice delayed tumor growth and prolonged survival. This novel mouse is proving to be a fascinating model with which to explore the biological consequences and clinical significance of Pik3caH1047R mutation in diverse tissue types and a valuable tool for the preclinical evaluation of PI3K pathway inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3289. doi:1538-7445.AM2012-3289