Title
A proteasome inhibitor, bortezomib, inhibits breast cancer growth and reduces osteolysis by downregulating metastatic genes
UMMS Affiliation
Department of Cell Biology; Department of Orthopedics and Physical Rehabilitation
Publication Date
2010-09-17
Document Type
Article
Subjects
Protease Inhibitors; Boronic Acids; Pyrazines; Breast Neoplasms; Osteolysis
Disciplines
Cell Biology
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.
DOI of Published Version
10.1158/1078-0432.CCR-09-3293
Source
Clin Cancer Res. 2010 Oct 15;16(20):4978-89. Epub 2010 Sep 15. Link to article on publisher's site
Journal/Book/Conference Title
Clinical cancer research : an official journal of the American Association for Cancer Research
Related Resources
PubMed ID
20843837
Repository Citation
Jones MD, Liu JC, Barthel TK, Hussain S, Lovria E, Cheng D, Schoonmaker JA, Mulay S, Ayers DC, Bouxsein ML, Stein GS, Mukherjee S, Lian JB. (2010). A proteasome inhibitor, bortezomib, inhibits breast cancer growth and reduces osteolysis by downregulating metastatic genes. Stein, Stein, Lian, vanWijnen Lab Publications. https://doi.org/10.1158/1078-0432.CCR-09-3293. Retrieved from https://escholarship.umassmed.edu/stein/6