Active Gαi/o mutants accelerate breast tumor metastasis via the c-Src pathway

Constitutively active mutations in the Gα_i2 and Gα_oA subunits of heterotrimeric G proteins have been identified in several human cancers including breast cancer, but their functional significance in tumorigenesis and metastasis has not been well characterized. In this study, we show that expression of the constitutively active Gα_oAR243H and Gα_i2R179C mutants alone was insufficient to induce mammary tumor formation in mice. However, in transgenic mouse models of breast cancer induced by Neu expression or PTEN loss, we found that the Gα_i2R179C mutant enhanced spontaneous lung metastasis while having no effect on primary tumor initiation and growth. Additionally, we observed that ectopic expression of the Gα_oAR243H and Gα_i2R179C mutants in tumor cells promote cell migration in vitro as well as dissemination into multiple organs in vivo by activating c-Src signaling. Thus, our study uncovers a critical function of Gα_i/o signaling in accelerating breast cancer metastasis via the c-Src pathway. This work is clinically significant, as it can potentially pave the way to personalized therapies for patients who present with active Gα_i/o mutations or elevated Gα_i/o signaling by targeting c-Src to inhibit breast cancer metastasis.