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

Abstract

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 microenvironment over a 3-to 4-week period as shown by [ 18 F]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. ©2010 AACR.Metastatic osteolytic disease is prevalent in cancer patients. In advanced breast cancer (BrCa), 70% of women develop osteolytic lesions, resulting in pain, pathologic fracture, and increased morbidity. Dysfunction of the ubiquitin-proteasome system is associated with tumor growth and metastatic disease, providing the rationale for development of proteasome inhibitors as antineoplastic therapies (1, 2). The proteasome is a ubiquitous enzyme complex that plays a critical role in the degradation of proteins involved in cell cycle regulation, apoptosis, and angiogenesis (2, 3). Bortezomib, a selective proteasome inhibitor used to treat multiple myeloma, has a potent anabolic effect on bone (4-9). Bortezomib alters the bone marrow microenvironment by increasing the number and differentiation of resident mesenchymal stem cells into osteoblasts, thereby increasing bone formation rates within 4 weeks in normal mice and resulting in trabecular bone formation in bone loss model (7). A similar enhancement of osteoblast differentiation is found in myeloma patients treated with bortezomib who show sustained increases in circulating osteocalcin, a marker of bone formation (6, 10). Thus, bortezomib treatment represents a novel and clinically feasible app...

Thyroid hormone regulates adhesion, migration and matrix metalloproteinase 9 activity via αvβ3 integrin in myeloma cells

“…The proteasome is a major cellular protease complex that controls the concentration and turnover of molecules in ECMs, including MMPs [37]. The down-regulation of MMP-9 protein levels by bortezomib, the first proteasome inhibitor in the clinic, has been documented in lung cancer [38], squamous cell carcinoma [39], bladder carcinoma [40], breast cancer cells [41] and myeloma cells [42]. The inhibition of MMP-9 by bortezomib may be due partly to blocking of the activation and nuclear translocation of NF-κB, which was reported to regulate MMP-9 transcription [43].…”

Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption

“…Then, the mice with similar osteolytic area were randomly divided into three groups for vehicle control or bortezomib treatment for another 70 days (n ¼ 6). We chose bortezomib dosages that were based on the clinical dosage scaled down for mice and are widely used in mouse models (32). Our results showed that, compared with normal mice, the vehicle control-treated mice displayed severe osteolytic lesions by X-ray NF-kB signaling pathway is highly activated in GCTB.…”

Proteasome inhibitor inhibits proliferation and induces apoptosis in renal interstitial fibroblasts

“…Pharmacological Reports, 2013, 65, 13571365 cellular signals and cell death, and the anti-tumor effects of a proteasome inhibitor have been extensively studied in multiple myeloma (MM) cells and other cancer cells [1,3,4,14,15,[23][24][25]. A proteasome inhibitor can inhibit the growth and proliferation of cancer cells and activate apoptosis [20].…”