A Critical Role of Gβγ in Tumorigenesis and Metastasis of Breast Cancer

A growing body of evidence indicates that G protein-coupled receptors (GPCRs) are involved in breast tumor progression and that targeting GPCRs may be a novel adjuvant strategy in cancer treatment. However, due to the redundant role of multiple GPCRs in tumor development, it may be necessary to target a common signaling component downstream of these receptors to achieve maximum efficacy. GPCRs transmit signals through heterotrimeric G proteins composed of G alpha and G beta gamma subunits. Here we evaluated the role of G beta gamma in breast tumor growth and metastasis both in vitro and in vivo. Our data show that blocking G beta gamma signaling with G alpha(t) or small molecule inhibitors blocked serum-induced breast tumor cell proliferation as well as tumor cell migration induced by various GPCRs in vitro. Moreover, induced expression of G alpha(t) in MDA-MB-231 cells inhibited primary tumor formation and retarded growth of existing breast tumors in nude mice. Blocking G beta gamma signaling also dramatically reduced the incidence of spontaneous lung metastasis from primary tumors and decreased tumor formation in the experimental lung metastasis model. Additional studies indicate that G beta gamma signaling may also play a role in the generation of a tumor microenvironment permissive for tumor progression, because the inhibition of G beta gamma signaling attenuated leukocyte infiltration and angiogenesis in primary breast tumors. Taken together, our data demonstrate a critical role of G beta gamma signaling in promoting breast tumor growth and metastasis and suggest that targeting G beta gamma may represent a novel therapeutic approach for breast cancer.