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

Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2011; 286(15):13244-54. DOI: 10.1074/jbc.M110.206615
Source: PubMed


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 Gα and Gβγ subunits. Here we evaluated the role of Gβγ in breast tumor growth and metastasis both in vitro and in vivo. Our data show that blocking Gβγ signaling with Gα(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 Gα(t) in MDA-MB-231 cells inhibited primary tumor formation and retarded growth of existing breast tumors in nude mice. Blocking Gβγ 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 Gβγ signaling may also play a role in the generation of a tumor microenvironment permissive for tumor progression, because the inhibition of Gβγ signaling attenuated leukocyte infiltration and angiogenesis in primary breast tumors. Taken together, our data demonstrate a critical role of Gβγ signaling in promoting breast tumor growth and metastasis and suggest that targeting Gβγ may represent a novel therapeutic approach for breast cancer.

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Available from: Frederick E Domann, Aug 29, 2014
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    • "After G-protein–coupled receptor activation, the release of G could thus direct the assembly of a G–Rap1a– Radil signaling complex, leading to spatiotemporal activation of integrins. Especially relevant to our findings showing that the depletion of Radil inhibits the metastasis of MDA-MB-231 cells to lungs, activation of the CXCR4 receptor (Müller et al., 2001) and G subunits (Kirui et al., 2010; Tang et al., 2011) were previously shown to be required for this process. Additionally, given that loss of function for the ERM protein ezrin was recently demonstrated to be required for the Rap1- induced spreading to similar extent than Radil (Ross et al., 2011), studying the functional relationship between these proteins may reveal further clues about their mechanisms. "
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    • "MDA-MB-231 cells, which were sensitive to mTRAIL in vitro and are able to metastasize spontaneously to lungs [23], were used to evaluate the in vivo effect of CD34-TRAIL+ cells. In experiment 1 (Fig. 3, experiment 1), NOD/SCID mice with established s.c. "
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