Active Gα Mutants Accelerate Breast Tumor Metastasis via the c-Src Pathway.

Constitutively active mutations in the Gα and Gα 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 GαR243H and GαR179C 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 GαR179C mutant notably enhanced spontaneous lung metastasis, without affecting primary tumor initiation and growth. Ectopic expression of the GαR243H and GαR179C mutants in tumor cells promoted cell migration and dissemination into multiple organs 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 subunits, which only partially overlap with those involved in inhibiting adenylyl cyclases. This study uncovers a critical role of Gα 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 mutations or elevated Gα signaling.