Molecular oncology 2017 03 15() doi 10.1002/1878-0261.12053
Although mutations in the phosphoinositide 3-kinase-catalytic subunit (PIK3CA) are common in breast cancer, PI3K inhibitors alone have shown modest efficacy. We sought to identify additional pathways altered in PIK3CA mutant tumors that might be targeted in combination with PI3K inhibitors. We generated two transgenic mouse models expressing the human PIK3CA-H1047R and the -E545K hotspot mutant genes in the mammary gland and evaluated their effects on development and tumor formation. Molecular analysis identified pathways altered in these mutant tumors, which were also targeted in multiple cells lines derived from the PIK3CA tumors. Finally, public databases were analyzed to determine if novel pathways identified in the mouse tumors were altered in human tumors harboring mutant PIK3CA. Mutant mice showed increased branching and delayed involution of the mammary gland compared to parental FVB/N mice. Mammary tumors arose in 30% of the MMTV-PIK3CA-H1047R and in 13% of -E545K mice. Compared to MMTV-Her-2 transgenic mouse mammary tumors, H1047R tumors showed increased upregulation of Wnt/β-Catenin/Axin2, hepatocyte growth factor (HGF)/STAT3, insulin-like growth factor 2 (IGF-2) and IGF-1R pathways. Inhibitors of STAT3,, β-catenin and IGF-1R sensitized H1047R-derived mouse tumor cells and PIK3CA-H1047R overexpressing human HS578T breast cancer cells to the cytotoxic effects of PI3K inhibitors. Analysis of The Cancer Genome Atlas (TCGA) database showed that, unlike primary PIK3CA-wildtype and HER-2(+) breast carcinomas, PIK3CA mutant tumors display increased expression of AXIN2, HGF, STAT3, IGF-1 and IGF-2 mRNA, and activation of AKT, IGF1-MTOR, and WNT canonical signaling pathways. Drugs targeting additional pathways that are altered in PIK3CA mutant tumors may improve treatment regimens using PI3K inhibitors alone. This article is protected by copyright. All rights reserved.