Abstract 5188: Phosphoinositide 3-kinase γ: Implications in breast cancer metastasis

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Abstract Metastasis is the major cause of breast cancer mortality. Type I phosphatidylinositol 3-kinases (PI3Ks), including α, β, γ and δ, play a pivotal role in diverse cell processes such as proliferation and motility. Of these PI3Ks, PI3Kγ is especially intriguing because it is: 1) normally expressed primarily in white blood cells which have a physiological need to migrate and 2) is specifically activated by G-protein coupled receptors (GPCRs). We recently reported that aberrant Gi-coupled receptor signaling promotes breast cancer metastasis (Xie et al., Cancer Res. 69: 5743-5751). The goal of the present study was to determine roles of PI3Kγ in breast cancer metastasis. We first examined the levels of PI3Kγ in different breast cancer cell lines by RT-PCR and Western blot analysis. We then immunohistochemically analyzed PI3Kγ protein expression in histologically benign and neoplastic cells of archival human breast tissues. We also investigated effects of PI3Ks inhibitors on migration and invasion abilities of breast cancer cells in Transwell chamber assays. Finally, we determined effects of PI3Ks inhibitors on lamellipodia formation, a key step involved in cancer metastasis. Our data indicated that PI3Kγ mRNA and protein were not detected in a normal human breast epithelial cell line (MCF-10A) or non-metastatic breast cancer cells (MCF-7 and T47D), but was found in metastatic breast cancer MDA-MB-231 cells and MDA-MB-436 cells. In contrast, PI3Kα, β and δ are ubiquitously expressed in these cell lines. In addition, immunohistochemical staining using a PI3Kγ-specific antibody showed that the expression of PI3Kγ protein was significantly increased in invasive human breast carcinoma and in breast cancer metastases to a regional lymph node as compared to the adjacent benign breast tissues or the noninvasive ductal carcinoma in situ. Thus, PI3Kγ expression level correlates with the metastatic potential of breast cancer cells. Interestingly, migration and invasion of metastatic breast cancer cells were inhibited by a selective inhibitor of PI3Kγ but not α or β isoforms. Furthermore, blocking PI3Kγ but not α and β disrupted the Rac-dependent lamellipodia formation induced by the activation of Gi-coupled receptor CXC chemokine receptor 4, but not epidermal growth factor tyrosine kinase receptor. Taken together, these results indicate that up-regulated PI3Kγ conveys the metastatic signal initiated from GPCRs in breast cancer cells and suggest that PI3Kγ may be a novel therapeutic target for the treatment of breast cancers. Supported by Nebraska State LB692 (YX). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5188.