Breast cancer migration and invasion depend on proteasome degradation of regulator of G-protein signaling 4

Yan Xie, Dennis W. Wolff, Taotao Wei, Bo Wang, Caishu Deng, Joseph K. Kirui, Haihong Jiang, Jianbing Qin, Peter W. Abel, Yaping Tu

Research output: Contribution to journalArticlepeer-review

99 Scopus citations


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 Gi-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 Gi-coupled receptors, thereby retarding the spread of breast cancer cells and making them targets for surgery, radiation, and immune treatment.

Original languageEnglish (US)
Pages (from-to)5743-5751
Number of pages9
JournalCancer Research
Issue number14
StatePublished - Jul 15 2009

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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