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Differential Functional Activation of Chemokine Receptor CXCR4 Is Mediated by G Proteins in Breast Cancer Cells

¹ School of Molecular and Biomedical Science, the University of Adelaide and ² Cytokine Receptor Laboratory, Institute of Medical and Veterinary Science, Adelaide, Australia

Requests for reprints: Shaun McColl, Chemokine Biology, School of Molecular and Biomedical Science, the University of Adelaide, Adelaide, South Australia 5005, Australia. Phone: 618-8303-4259; Fax: 618-8303-3337; E-mail: shaun.mccoll{at}adelaide.edu.au.

CXCR4 is a G protein–coupled receptor of considerable biological significance, and among its numerous functions, it is suggested to play a critical role in cancer metastasis. We have investigated the expression and function of CXCR4 in a range of breast cancer cell lines covering a spectrum of invasive phenotypes and found that, while surface levels of CXCR4 were uniform across the entire panel, only highly invasive cells that are metastatic in immunocompromised mice expressed functional receptors. CXCL12/SDF-1 induced cellular responses such as calcium mobilization, actin polymerization, and chemotaxis in metastatic cells, whereas noninvasive cells were unresponsive. Moreover, CXCL12 activated multiple signaling pathways downstream of G proteins in highly invasive cells but failed to activate any of the examined kinase cascades in noninvasive cell lines. This blockade in nonmetastatic cell lines seems to be due to the inability of G protein and ß subunits to form a heterotrimeric complex with CXCR4. G and Gß were able to bind to CXCR4 independently in all cell lines, but the association of G protein ß heterotrimers with the receptor, a prerequisite for signal transduction downstream from G protein–coupled receptors, was only observed in the highly invasive cell lines. Our findings show, for the first time, that CXCR4 function is subject to complex and potentially tightly controlled regulation in breast cancer cells via differential G protein–receptor complex formation, and this regulation may play a role in the transition from nonmetastatic to malignant tumors. (Cancer Res 2006; 66(8): 4117-24)

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