Cathepsin B inhibition limits bone metastasis in breast cancer

Metastasis to bone is a major cause of morbidity in breast Cancer patients, emphasizing the importance of identifying molecular drivers of bone metastasis for new therapeutic targets. The endogenous cysteine Cathepsin Inhibitor stefin A is a suppressor of breast Cancer metastasis to bone that is coexpressed with Cathepsin B in bone metastases. In this study, we used the immunocompetent 4T1.2 model of breast Cancer which exhibits spontaneous bone metastasis to evaluate the function and therapeutic targeting potential of Cathepsin B in this setting of advanced disease. Cathepsin B abundancy in the model mimicked human disease, both at the level of primary tumors and matched spinal metastases. RNA interference-mediated knockdown of Cathepsin B in tumor cells reduced collagen I degradation in vitro and bone metastasis in vivo. Similarly, intraperitoneal administration of the highly selective Cathepsin B Inhibitor CA-074 reduced metastasis in tumor-bearing Animals, a reduction that was not reproduced by the broad spectrum cysteine Cathepsin Inhibitor JPM-OEt. Notably, metastasis suppression by CA-074 was maintained in a late treatment setting, pointing to a role in metastatic outgrowth. Together, our findings established a prometastatic role for Cathepsin B in distant metastasis and illustrated the therapeutic benefits of its selective inhibition in vivo.