TY - JOUR AB - Though incidence of PI3K oncogenic mutation is prominent in breast cancer (20-30%), pharmacological targeting of this signaling pathway alone has failed to provide meaningful clinical benefit. To better understand and address this problem, we conducted genome-wide analysis to study the association of mutant PI3K with other gene amplification events. One of the most significant copy number gain events associated with PIK3CA mutation was the region within chromosome 17 containing HER2. To investigate the oncogenic effect and cell signaling regulation of co-occurring PIK3CA-H1047R and or HER2 gene, we generated cell models ectopically expressing mutant PIK3CA, HER2 or both genetic alterations. We observed that cells with both genetic alterations demonstrate increased aggressiveness and invasive capabilities than cells with either genetic change alone. Furthermore, we found that the combination of the HER2 inhibitor (CP-724714) and pan PI3K inhibitor (LY294002) is more potent than either inhibitor alone in terms of inhibition of cell proliferation and colony formation. Significantly, four cell signaling pathways were found in common for cells with HER2, mutant PIK3CA and cells with both genetic alterations through an Affymetric microarray analysis. Moreover, the cells with both genetic alterations acquired more significant replication stress as shown by enriched signaling pathways of cell cycle checkpoint control and DNA damage response signaling. Our study suggests co-occurrence of oncogenic HER2 and mutant PIK3CA cooperatively drives breast cancer progression. The cells with both genetic alterations obtain additional features of replication stress which could open new opportunity for cancer diagnostics and treatment. AD - Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn Mount Sinai School of Medicine, New York, NY 10029, USA Department of Breast Surgery, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China AU - Dong,Lun AU - Meng,Fanyan AU - Wu,Ling AU - Mitchell,Allison ,V. AU - Block,C. ,James AU - Zhang,Bin AU - Craig,Douglas ,B. AU - Jang,Hyejeong AU - Chen,Wei AU - Yang,Qifeng AU - Wu,Guojun DA - 2017/10/01 DO - 10.3892/ijo.2017.4108 EP - 1330 IS - 4 JO - Int J Oncol KW - PIK3CA HER2 breast cancer gene amplification PY - 2017 SN - 1019-6439 1791-2423 SP - 1320 ST - Cooperative oncogenic effect and cell signaling crosstalk of co‑occurring HER2 and mutant PIK3CA in mammary epithelial cells T2 - International Journal of Oncology TI - Cooperative oncogenic effect and cell signaling crosstalk of co‑occurring HER2 and mutant PIK3CA in mammary epithelial cells UR - https://doi.org/10.3892/ijo.2017.4108 VL - 51 ER -