Abstract 2603: A critical role of Gβγ in breast tumor growth and metastasis

Abstract

Abstract A growing body of evidence indicates the involvement of G protein coupled receptors (GPCRs) in the process of breast tumor development, including tumor growth, invasion and metastasis. Targeting GPCRs has been proposed as a novel adjuvant strategy in cancer treatment. However, this approach faces many significant hurdles due in part to the involvement of multiple GPCRs in tumor progression. Thus, there is a need for an alternative approach that targets a signaling mechanism common to these receptors. GPCRs such as lysophosphatidic acid (LPA) receptors, thrombin receptors and the chemokine receptor CXCR4 transmit signals through multiple classes of heterotrimeric G proteins, which consist of Gα and Gβγ subunits. There are four major classes of Gα subunits (Gαi, Gαs, Gαq and Gα12/13) that regulate distinct activities of different effectors. Although there are 5 Gβ and 12 Gγ isoforms, different combination of Gβγ complexes appear to regulate a similar profile of downstream effectors. We therefore reason that Gβγ-dependent signaling may represent a point of signal convergence from multiple GPCRs that can be targeted for the therapeutic of breast tumor. In this study, we evaluated the role of Gβγ in breast tumor progression. Our data show that blocking Gβγ signaling with small molecular inhibitors alleviated breast tumor cell proliferation and GPCR-stimulated cell migration in vitro, suggesting that Gβγ is critical for breast tumor progression. Consistent with these findings, overexpression of Gβγ scavengers, the C-terminal tail of G protein-coupled receptor kinase 2 (GRK2-ct) or Gαt, in breast tumor cells suppressed tumor cell growth both in 2D and 3D culture, and abolished LPA- and SDF1α-stimulated cell migration. Additional studies indicate that Gβγ mediates GPCR-simulated activation of PI3K, PLCβ and MAPK, which in turn contribute to breast tumor cell growth and migration. Finally, by inducible expression of Gαt in MDA-MB-231 cells, we provided evidence that Gβγ signaling promotes tumor cell growth and lung metastasis in mouse xenograft models. Taken together, our data demonstrate that Gβγ plays a critical role in breast tumor progression. These findings suggest that targeting Gβγ-dependent signaling may represent a novel therapeutic approach for breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2603.