Breast cancer metastasis suppressor 1 inhibits gene expression by targeting nuclear factor-kappaB activity

Cancer Res. 2005 May 1;65(9):3586-95. doi: 10.1158/0008-5472.CAN-04-3139.

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

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic / physiology*
  • Humans
  • I-kappa B Kinase
  • I-kappa B Proteins / antagonists & inhibitors
  • I-kappa B Proteins / biosynthesis
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Lung Neoplasms / secondary
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mice
  • Mice, Nude
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / genetics
  • NF-kappa B / physiology
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Phosphorylation
  • Protein Serine-Threonine Kinases / biosynthesis
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Repressor Proteins
  • Transfection
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism
  • Urokinase-Type Plasminogen Activator / biosynthesis
  • Urokinase-Type Plasminogen Activator / genetics

Substances

  • BRMS1 protein, human
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Neoplasm Proteins
  • Nfkbia protein, mouse
  • RNA, Messenger
  • Repressor Proteins
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Protein Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • Urokinase-Type Plasminogen Activator