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Targeting G protein‐coupled receptor signaling to suppress breast cancer metastasis

Excessive signaling from G protein‐coupled receptors (GPCRs) promotes metastasis, the major cause of breast cancer death. Since breast cancer metastasis could be driven by different GPCRs simultaneously, identifying downstream molecules that regulate signals initiated by multiple GPCRs could be an effective, alternative strategy to suppress breast cancer metastasis. GPCRs convey signals via G proteinsin the form of Gα and Gβγ subunits. We found that PI3Kγ, a Gβγ down‐stream effector, was up‐regulated in metastatic breast cancer cells and human invasive breast carcinoma. Blockade of PI3Kγ suppressed breast cancer metastatic abilities. In addition, RGS4, an intracellular regulator of GPCRs, attenuates PI3Kγ activation induced by multiple metastasis‐promoting GPCRs. However, RGS4 protein was down‐regulated in metastatic breast cancer cells due to oxidation‐induced proteasome degradation. Restoring RGS4 expression suppressed breast cancer invasion in vitro and in a mouse xenograft. Interestingly, RGS4 degradation is dependent on PI3Kγ‐stimulated production of reactive oxygen species. PI3Kγ inhibitors or antioxidants protect RGS4 from degradation in breast cancer cells. Thus, a combination of a PI3Kγ inhibitor and antioxidants could be a superior treatment strategy for preventing breast cancer metastasis. Supported by NIH (R011CA125661) and Nebraska State LB595.