Abstract Breast cancer exhibits a propensity to metastasize to bone, resulting in debilitating skeletal-related complications associated with significant morbidity and mortality. Because of the clinical significance of this process, many research efforts are aimed at uncovering the molecular events in bone metastases to identify novel targets and to improve clinical management of metastatic bone disease. The interactions between metastatic cells and bone are critical to the development and progression of bone metastases, and their unravelling could lead to novel preventive or therapeutic approaches. We previously demonstrated the critical role of HGF/c-Met/β-catenin/TCF system in tumor-bone interaction leading to skeletal metastases of human breast cancer cells, suggesting the potential inhibition of this pathway in vivo. In this study, we evaluated the potential therapeutic efficacy of targeting the c-Met receptor by using both an oral, selective, small-molecule c-Met inhibitor, tivantinib, and a specific shRNA against c-Met in an experimental bone metastatic model of human breast cancer. Tivantinib exhibited dose-dependent anti-metastatic activity in vivo, and the 120 mg/kg dose, while being ineffective in reducing subcutaneous tumor growth, induced significant inhibition of bone metastatic growth and a noteworthy reduction of tumor-induced osteolysis. shRNA-mediated c-Met silencing did not affect in vitro proliferation of bone metastatic cells, but strongly reduced their migration, and this effect was further enhanced by tivantinib. These data were confirmed in vivo. Indeed, dual c-Met inhibition with both tivantinib and RNA interference strategy induces pronounced tumor growth suppression with concomitant marked decreases of lytic lesions and an improvement in survival. Overall, our findings highlighted the efficacy of c-Met inhibition in delaying the onset and progression of bone metastases and strongly suggested that targeting the c-Met receptor may have promising therapeutic value in the prevention and treatment of bone metastases from breast cancer. Most importantly, the finding that tivantinib is active as an anti-metastatic agent at low, non-cytotoxic doses suggests that its efficacy may be potentiated by combining it with other therapies that target cancer cell-bone interactions. Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 846. doi:1538-7445.AM2012-846