Breast Cancer Metastasis Depends on Proteasome Degradation of Regulator of G‐protein Signaling 4

Abstract

Aberrant signaling through G‐protein coupled receptors promotes metastasis, the major cause of breast cancer death. We identified Regulator of G‐protein Signaling 4 (RGS4) as a novel metastasis suppressor. By blocking signals initiated through Gi‐coupled receptors, such as protease‐activated receptor 1 and CXC chemokine receptor 4, via its GTPase Activating Protein (GAP) activity, RGS4 disrupted Rac1‐dependent lamellipodia formation, a key step involved in metastasis. An RGS4 GAP‐deficient mutant failed to inhibit the metastatic abilities of breast cancer cells in both in vitro and a mouse xenograft model. Interestingly, both established breast cancer cell lines and human breast cancer specimens showed that the highest levels of RGS4 protein were expressed in normal breast epithelia and that RGS4 down‐regulation by proteasome degradation is an index of breast cancer metastasis. Proteasome blockade increases endogenous RGS4 protein to levels that markedly inhibit breast cancer cell migration and invasion, which could be reversed by an RGS4‐targeted shRNA. Our findings point to the existence of a mechanism for posttranslational regulation of RGS4 function, which may have important implications for the acquisition of a metastatic phenotype by breast cancer. Preventing RGS4 degradation should retard the spread of breast cancer cells and making them targets for surgery, radiation and immune treatment.