β-arrestin1 mediates metastatic growth of breast cancer cells by facilitating HIF-1-dependent VEGF expression

beta-Arrestins 1 and 2 are multifunctional adaptor proteins originally discovered for their role in desensitizing seven-transmembrane receptor signaling via the heterotrimeric guanine nucleotide-binding proteins. Recently identified roles of beta-arrestins include regulation of cancer cell chemotaxis and proliferation. Herein, we report that beta-arrestin1 expression regulates breast tumor colonization in nude mice and cancer cell viability during hypoxia. beta-Arrestin1 robustly interacts with nuclear hypoxia-induced factor-1 alpha (HIF-1 alpha) that is stabilized during hypoxia and potentiates HIF-1-dependent transcription of the angiogenic factor vascular endothelial growth factor-A (VEGF-A). Increased expression of beta-arrestin1 in human breast cancer (infiltrating ductal carcinoma or IDC and metastatic IDC) correlates with increased levels of VEGF-A. While the anti-angiogenic drug thalidomide inhibits HIF-1-dependent VEGF transcription in breast carcinoma cells, it does not prevent HIF-1 alpha stabilization, but leads to aberrant localization of HIF-1 alpha to the perinuclear compartments and surprisingly stimulates nuclear export of beta-arrestin1. Additionally, imatinib mesylate that inhibits release of VEGF induces nuclear export of beta-arrestin1-HIF-1 alpha complexes. Our findings suggest that beta-arrestin1 regulates nuclear signaling during hypoxia to promote survival of breast cancer cells via VEGF signaling and that drugs that induce its translocation from the nucleus to the cytoplasm could be useful in anti-angiogenic and breast cancer therapies. Oncogene (2012) 31, 282-292; doi:10.1038/onc.2011.238; published online 20 June 2011