Up‐regulated phosphoinositide 3‐kinase γ (PI3Kγ ) promotes breast cancer metastasis

We recently reported that dysregulation of G i ‐coupled receptors promotes breast cancer metastasis via Rac‐dependent pathways (Xie et al., Cancer Res. 69: 5743–5751). The PI3K γ is selctively activated by G i ‐coupled receptors. The objective of this study was to define the role of PI3K γ in breast cancer metastasis. Immunohistochemical staining and Western blot analysis showed that PI3K γ expression was selectively up‐regulated in human metastatic breast cancer cell line and breast cancer specimens. Transwell chamber assays indicated that migration and invasion of metastatic breast cancer cells in response to chemoattractants of NIH‐3T3 conditioned media was inhibited by a selective inhibitor of PI3K γ but not PI3K α or β isoforms. Furthermore, blocking PI3K γ not PI3K α and β disrupted the Rac‐dependent lamellipodia formation induced by the activation of G i ‐coupledreceptors, such as protease‐activated receptor 1 and CXC chemokinereceptor 4. In contrast, the lamellipodia formation induced by epidermal growth factor (EGF), a process not dependent on G‐proteins, was blocked by inhibitors of PI3K α and β not by the PI3Kγ Inhibitor. Our data demonstrated that PI3Kγ functions as a key molecule mediating signal flow from G i ‐coupled receptors to Rac‐dependent pathways and suggests that PI3K γ may be a novel therapeutic target for the treatment of breast cancers. Supported by Nebraska State LB692 (YX).