Co-expression of cathepsin B and its inhibitor Stefin A in breast cancer metastasis to lung and bone

3095 Metastatic breast cancer is a life threatening disease with limited treatment options. Given the lack of molecular targets for tailored therapy, we analysed changes in gene expression associated with metastatic progression in breast cancer using a clinically relevant murine model of spontaneous metastasis to lung and bone. From microarray expression profiling of immunopurified tumor cells derived from primary tumors and matched metastases, we identified the cysteine cathepsin inhibitor Stefin A. Stefin A expression was increased in neoplastic epithelial cells isolated from metastatic primary tumors and further increased in their matched spontaneous metastases in lung and bone in the mouse model. Expression was not detected in tumor cells in culture, indicating induction within the tumor microenvironment. To establish a link with the clinical disease we investigated Stefin A expression in human breast cancer tissues. Breast cancer patients (n=24) lacking primary tumor expression of Stefin A had improved disease free survival (p=0.017). In patients who had recurrent disease, Stefin A was enhanced in lung and bone metastases. Stefin A may be a marker of enhanced cathepsin activity, since cathepsin B activity was increased in highly metastatic primary tumors. Additionally, Stefin A and cathepsin B were co-expressed in primary tumors and lung and bone metastases, both in the murine model and in human tissues. We conclude that Stefin A is expressed in metastatic breast tumors and in distant metastases, acting as a marker of activated cysteine cathepsins, which are potential therapeutic targets for metastatic disease.