The role of β-arrestins in cancer.

Beyond their well-characterized roles in G protein-coupled receptor desensitization and trafficking, β-arrestins (ARRBs) have been implicated in the regulation of several basic cellular functions, including cell cycle regulation, cell migration, and apoptotic signaling. Nowhere are the data supporting a physiologically relevant role for these arrestin-mediated responses stronger than in cancer. In vitro, ARRBs regulate cell proliferation, promote migration, and transmit anti-apoptotic survival signals by scaffolding cytosolic signaling protein networks and even translocating to the nucleus to directly regulate gene expression. In animal models, ARRB expression affects tumor initiation time, growth rate, vascularization, survival under hypoxic conditions, invasiveness, and metastatic potential. Studies in human cancer patients have demonstrated that dysregulation of ARRB expression, localization, or phosphorylation is associated with more aggressive cancer phenotypes and poorer outcomes in malignancies involving the breast, lung, prostate, brain, and hematologic system. Collectively, these data build a strong case that ARRB-dependent signaling contributes to the cancer phenotype and that the ARRBs may represent novel therapeutic targets in certain malignancies.