Abstract
Constitutively active mutations in the Gαi2 and GαoA 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 GαoAR243H and Gαi2R179C 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 Gαi2R179C mutant notably enhanced spontaneous lung metastasis, without affecting primary tumor initiation and growth. Ectopic expression of the GαoAR243H and Gαi2R179C 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 Gαi subunits, which only partially overlap with those involved in inhibiting adenylyl cyclases. This study uncovers a critical role of Gαi/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 Gαi/o mutations or elevated Gαi/o signaling.