Abstract
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-kappaB (NF-kappaB). To further investigate the role of NF-kappaB in BRMS1-regulated gene expression, we examined NF-kappaB binding activity and found an inverse correlation between BRMS1 expression and NF-kappaB 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-alpha-induced NF-kappaB activation by BRMS1 may be due to inhibition of IkappaBalpha 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-kappaB activity and subsequent suppression of uPA expression in breast cancer and melanoma cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Down-Regulation
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Gene Expression Regulation, Neoplastic / genetics
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Gene Expression Regulation, Neoplastic / physiology*
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Humans
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I-kappa B Kinase
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I-kappa B Proteins / antagonists & inhibitors
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I-kappa B Proteins / biosynthesis
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I-kappa B Proteins / genetics
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I-kappa B Proteins / metabolism
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Lung Neoplasms / secondary
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Melanoma / genetics*
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Melanoma / metabolism
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Melanoma / pathology
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Mice
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Mice, Nude
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NF-KappaB Inhibitor alpha
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / genetics
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NF-kappa B / physiology
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Phosphorylation
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Repressor Proteins
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Transfection
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / metabolism
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Urokinase-Type Plasminogen Activator / biosynthesis
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Urokinase-Type Plasminogen Activator / genetics
Substances
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BRMS1 protein, human
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I-kappa B Proteins
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NF-kappa B
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NFKBIA protein, human
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Neoplasm Proteins
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Nfkbia protein, mouse
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RNA, Messenger
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Repressor Proteins
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Tumor Necrosis Factor-alpha
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NF-KappaB Inhibitor alpha
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Protein Serine-Threonine Kinases
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse
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Urokinase-Type Plasminogen Activator