Transforming growth factor-β signaling at the tumor-bone interface promotes mammary tumor growth and osteoclast activation

Understanding the cellular and molecular changes in the bone microenvironment is important for developing novel therapeutics to control breast cancer bone metastasis. Although the underlying mechanism(s) of bone metastasis has been the focus of intense investigation, relatively little is known about complex molecular interactions between malignant cells and bone stroma. Using a murine syngeneic model that mimics osteolytic changes associated with human breast cancer, we examined the role of tumor-bone interaction in tumor-induced osteolysis and malignant growth in the bone microenvironment. We identified transforming growth factor-β receptor 1 (TGF-βRI) as a commonly upregulated gene at the tumor-bone (TB) interface. Moreover, TGF-βRI expression and activation, analyzed by nuclear localization of phospho-Smad2, was higher in tumor cells and osteoclasts at the TB interface as compared to the tumor-alone area. Furthermore, attenuation of TGF-β activity by neutralizing antibody to TGF-β or TGF-βRI kinase inhibitor reduced mammary tumor-induced osteolysis, TGF-βRI expression and its activation. In addition, we demonstrate a potential role of TGF-β as an important modifier of receptor activator of NF-κB ligand (RANKL)-dependent osteoclast activation and osteolysis. Together, these studies demonstrate that inhibition of TGF-βRI signaling at the TB interface will be a therapeutic target in the treatment of breast cancer-induced osteolysis.