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

Abstract

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␣ and G␤␥ subunits. Here we evaluated the role of G␤␥ in breast tumor growth and metastasis both in vitro and in vivo. Our data show that blocking G␤␥ signaling with G␣ 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␣ t in MDA-MB-231 cells inhibited primary tumor formation and retarded growth of existing breast tumors in nude mice. Blocking G␤␥ 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␤␥ signaling may also play a role in the generation of a tumor microenvironment permissive for tumor progression, because the inhibition of G␤␥ signaling attenuated leukocyte infiltration and angiogenesis in primary breast tumors. Taken together, our data demonstrate a critical role of G␤␥ signaling in promoting breast tumor growth and metastasis and suggest that targeting G␤␥ may represent a novel therapeutic approach for breast cancer.Breast cancer is the most frequently diagnosed cancer in women (1). Despite recent advances in its diagnosis and treatment with adjuvant targeted therapies, breast cancer remains the second most common cause of cancer death among women in the United States (2). As many as 90% of cancer deaths are caused by metastatic spread from primary tumors because the majority of currently marketed anticancer drugs have little effect on tumors at this stage. In light of this situation, efforts to better understand the mechanisms underlying tumor metastasis and to identify novel treatment strategies are warranted.

WDR26 Functions as a Scaffolding Protein to Promote Gβγ-mediated Phospholipase C β2 (PLCβ2) Activation in Leukocytes

“…Moreover, our previous work has already demonstrated that the regulation of G␤␥ signaling by WDR26 is critical for leukocyte migration (16). Recent work has shown that G␤␥ signaling is also involved in numerous pathological conditions such as heart failure and tumor growth and metastasis (5,33). It would be interesting to determine whether aberrant regulation of G␤␥ signaling by WDR26 contributes to these pathological conditions.…”

“…In addition, they directly interact with and modulate the activity of a long list of proteins including receptors, ion channels, and enzymes such as PLC, 2 phosphoinositide 3-kinases (PI3Ks), and G protein-coupled receptor kinase 2. Through these downstream targets, G␤␥ regulates diverse functions including immune and tumor cell migration (3)(4)(5), yeast cell mating (6), and heart rate (7).…”

Inhibition of the Ethanol-induced Potentiation of α1 Glycine Receptor by a Small Peptide That Interferes with Gβγ Binding

“…G␤␥ signaling is recognized to be important in several physiopathological conditions such as heart failure (42), tumorigenesis (43), cell migration and invasion (44), pharmacological tolerance and dependence (45), inflammatory processes (46), and several endocrine pathologies (47,48), among others. One of the first attempts at blocking the function of G␤␥ with selective peptides was developed for adenylyl cyclase.…”

WD40-repeat proteins control the flow of Gβγ signaling for directional cell migration

“…35,36 Conceivably, aberrant regulation of Gβγ signaling by WDR26 and RACK1 may contribute to tumor progression. Indeed, translocation suggest that active Gαi/o and/or Gβγ signaling is required for translocation.…”