A Proteasome Inhibitor, Bortezomib, Inhibits Breast Cancer Growth and Reduces Osteolysis by Downregulating Metastatic Genes

Purpose: The incidence of bone metastasis in advanced breast cancer (BrCa) exceeds 70%. Bortezomib, a proteasome inhibitor used for the treatment of multiple myeloma, also promotes bone formation. We tested the hypothesis that proteasome inhibitors can ameliorate BrCa osteolytic disease. Experimental Design: To address the potentially beneficial effect of bortezomib in reducing tumor growth in the skeleton and counteracting bone osteolysis, human MDA-MB-231 BrCa cells were injected into the tibia of mice to model bone tumor growth for in vivo assessment of treatment regimens before and after tumor growth. Results: Controls exhibited tumor growth, destroying trabecular and cortical bone and invading muscle. Bortezomib treatment initiated following inoculation of tumor cells strikingly reduced tumor growth, restricted tumor cells mainly to the marrow cavity, and almost completely inhibited osteolysis in the bone micro-environment over a 3-to 4-week period as shown by [F-18] fluorodeoxyglucose positron emission tomography, micro-computed tomography scanning, radiography, and histology. Thus, proteasome inhibition is effective in killing tumor cells within the bone. Pretreatment with bortezomib for 3 weeks before inoculation of tumor cells was also effective in reducing osteolysis. Our in vitro and in vivo studies indicate that mechanisms by which bortezomib inhibits tumor growth and reduces osteolysis result from inhibited cell proliferation, necrosis, and decreased expression of factors that promote BrCa tumor progression in bone. Conclusion: These findings provide a basis for a novel strategy to treat patients with BrCa osteolytic lesions, and represent an approach for protecting the entire skeleton from metastatic bone disease. Clin Cancer Res; 16(20); 4978-89. (C) 2010 AACR.