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 suppressor of
breast cancer migration and invasion, important steps of metastatic cascades. By blocking signals initiated through G(i)-coupled receptors, such as
protease-activated receptor 1 and
CXC chemokine receptor 4, RGS4 disrupted Rac1-dependent lamellipodia formation, a key step involved in
cancer migration and invasion. RGS4 has
GTPase-activating protein (GAP) activity, which inhibits
G-protein coupled receptor signaling by deactivating
G-proteins. An RGS4 GAP-deficient mutant failed to inhibit migration and invasion of
breast cancer cells in both in vitro assays 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 invasiveness.
Proteasome blockade increased endogenous
RGS4 protein to levels that markedly inhibit
breast cancer cell migration and invasion, which was reversed by an RGS4-targeted
short hairpin RNA. 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 cells. Preventing degradation of
RGS4 protein should attenuate aberrant signal inputs from multiple G(i)-coupled receptors, thereby retarding the spread of
breast cancer cells and making them targets for surgery, radiation, and immune treatment.