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Breast Cancer Metastasis Suppressor 1 Inhibits Gene Expression by Targeting Nuclear Factor-B Activity

¹ Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Lerner School of Medicine, Cleveland, Ohio and ² Department of Pathology, Comprehensive Cancer Center, and National Foundation for Cancer Research Center for Metastasis Research, University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Graham Casey, Department of Cancer Biology, ND50, Lerner Research Institute, Cleveland Clinic Lerner School of Medicine, 9500 Euclid Avenue, Cleveland, OH 44195. Phone: 216-445-9754; Fax: 216-445-0610; E-mail: caseyg{at}ccf.org.

Breast cancer metastasis suppressor 1 (BRMS1) functions as a metastasis suppressor gene in breast cancer and melanoma cell lines, but the mechanism of BRMS1 suppression remains unclear. We determined that BRMS1 expression was inversely correlated with that of urokinase-type plasminogen activator (uPA), a prometastatic gene that is regulated at least in part by nuclear factor-B (NF-B). To further investigate the role of NF-B in BRMS1-regulated gene expression, we examined NF-B binding activity and found an inverse correlation between BRMS1 expression and NF-B binding activity in MDA-MB-231 breast cancer and C8161.9 melanoma cells stably expressing BRMS1. In contrast, BRMS1 expression had no effect on activation of the activator protein-1 transcription factor. Further, we showed that suppression of both constitutive and tumor necrosis factor-–induced NF-B activation by BRMS1 may be due to inhibition of IB phosphorylation and degradation. To examine the relationship between BRMS1 and uPA expression in primary breast tumors, we screened a breast cancer dot blot array of normalized cDNA from 50 breast tumors and corresponding normal breast tissues. There was a significant reduction in BRMS1 mRNA expression in breast tumors compared with matched normal breast tissues (paired t test, P < 0.0001) and a general inverse correlation with uPA gene expression (P < 0.01). These results suggest that at least one of the underlying mechanisms of BRMS1-dependent suppression of tumor metastasis includes inhibition of NF-B activity and subsequent suppression of uPA expression in breast cancer and melanoma cells.

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