Merino Vanessa F, Cho Soonweng, Liang Xiaohui, Park Sunju, Jin Kideok, Chen Qian, Pan Duojia, Zahnow Cynthia A, Rein Alan R, Sukumar Saraswati
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Mol Oncol. 2017 May;11(5):552-566. doi: 10.1002/1878-0261.12053. Epub 2017 Apr 6.
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 cell lines derived from the PIK3CA tumors. Finally, public databases were analyzed to determine whether 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 database showed that, unlike primary PIK3CA-wild-type 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.
尽管磷酸肌醇3激酶催化亚基（PIK3CA）的突变在乳腺癌中很常见，但单独使用PI3K抑制剂的疗效并不显著。我们试图确定PIK3CA突变肿瘤中其他发生改变的通路，这些通路可能与PI3K抑制剂联合使用时作为靶点。我们构建了两种在乳腺中表达人PIK3CA-H1047R和-E545K热点突变基因的转基因小鼠模型，并评估它们对发育和肿瘤形成的影响。分子分析确定了这些突变肿瘤中发生改变的通路，这些通路在源自PIK3CA肿瘤的多种细胞系中也有靶点。最后，分析公共数据库以确定在小鼠肿瘤中鉴定出的新通路在携带突变PIK3CA的人类肿瘤中是否发生改变。与亲本FVB/N小鼠相比，突变小鼠的乳腺分支增加且退化延迟。30%的MMTV-PIK3CA-H1047R小鼠和13%的-E545K小鼠发生乳腺肿瘤。与MMTV-Her-2转基因小鼠乳腺肿瘤相比，H1047R肿瘤显示Wnt/β-连环蛋白/Axin2、肝细胞生长因子（Hgf）/Stat3、胰岛素样生长因子2（Igf-2）和Igf-1R通路的上调增加。STAT3、β-连环蛋白和IGF-1R的抑制剂使源自H1047R的小鼠肿瘤细胞和过表达PIK3CA-H1047R的人HS578T乳腺癌细胞对PI3K抑制剂的细胞毒性作用敏感。癌症基因组图谱数据库分析表明，与原发性PIK3CA野生型和HER-2乳腺癌不同，PIK3CA突变肿瘤显示AXIN2、HGF、STAT3、IGF-1和IGF-2 mRNA表达增加以及AKT、IGF1-MTOR和WNT经典信号通路的激活。针对PIK3CA突变肿瘤中其他发生改变的通路的药物可能会改善单独使用PI3K抑制剂的治疗方案。
