Active Gα_i/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 found in various human cancers, including breast cancer, but their precise roles in tumor formation, progression, and metastasis remain poorly understood. This study focused on Gα_oAR243H and Gα_i2R179C mutants in breast cancer. These mutants alone were insufficient to initiate mammary tumor formation in mice. However, when introduced into transgenic mouse models of breast cancer induced by Neu expression or PTEN loss, the Gα_i2R179C mutant notably enhanced spontaneous lung metastasis, without affecting primary tumor initiation and growth. Ectopic expression of the Gα_oAR243H and Gα_i2R179C mutants in tumor cells promoted cell migration in vitro and dissemination into multiple organs in vivo by activating the c-Src signaling pathway. These mutants activate c-Src through direct interaction, involving specific residues in the switch domains II of Gα_i subunits, which only partially overlap with those involved in inhibiting adenylyl cyclases. This study uncovers a critical role of Gα_i/o signaling in accelerating breast cancer metastasis through the c-Src pathway. These findings hold clinical significance as they may pave the way for personalized therapies targeting c-Src to inhibit breast cancer metastasis in patients with active Gα_i/o mutations or elevated Gα_i/o signaling.