Identification of upregulated phosphoinositide 3-kinase γ as a target to suppress breast cancer cell migration and invasion

Metastasis is the major cause of breast cancer mortality. We recently reported that aberrant G-protein coupled receptor (GPCR) signaling promotes breast cancer metastasis by enhancing cancer cell migration and invasion. Phosphatidylinositol 3-kinase gamma (PI3K gamma) is specifically activated by GPCRs. The goal of the present study was to determine the role of PI3K gamma in breast cancer cell migration and invasion. Immunohistochemical staining showed that the expression of PI3K gamma protein was significantly increased in invasive human breast carcinoma when compared to adjacent benign breast tissue or ductal carcinoma in situ. PI3K gamma was also detected in metastatic breast cancer cells, but not in normal breast epithelial cell line or in non-metastatic breast cancer cells. In contrast, PI3K isoforms alpha, beta and delta were ubiquitously expressed in these cell lines. Overexpression of recombinant PI3K gamma enhanced the metastatic ability of non-metastatic breast cancer cells. Conversely, migration and invasion of metastatic breast cancer cells were inhibited by a PI3K gamma inhibitor or by siRNA knockdown of PI3K gamma but not by inhibitors or siRNAs of PI3K alpha or PI3K beta. Lamellipodia formation is a key step in cancer metastasis, and PI3K gamma blockade disrupted lamellipodia formation induced by the activation of GPCRs such as CXC chemokine receptor 4 and protease-activated receptor 1, but not by the epidermal growth factor tyrosine kinase receptor. Taken together, these results indicate that upregulated PI3K gamma conveys the metastatic signal initiated by GPCRs in breast cancer cells, and suggest that PI3K gamma may be a novel therapeutic target for development of chemotherapeutic agents to prevent breast cancer metastasis. (c) 2013 Elsevier Inc. All rights reserved.