Breast cancer metastasis suppressor 1 (BRMS1) inhibits osteopontin transcription by abrogating NF-kappaB activation

Mol Cancer. 2007 Jan 16;6:6. doi: 10.1186/1476-4598-6-6.

Abstract

Background: Osteopontin (OPN), a secreted phosphoglycoprotein, has been strongly associated with tumor progression and aggressive cancers. MDA-MB-435 cells secrete very high levels of OPN. However metastasis-suppressed MDA-MB-435 cells, which were transfected with breast cancer metastasis suppressor 1 (BRMS1), expressed significantly less OPN. BRMS1 is a member of mSin3-HDAC transcription co-repressor complex and has been shown to suppress the metastasis of breast cancer and melanoma cells in animal models. Hence we hypothesized that BRMS1 regulates OPN expression.

Results: The search for a BRMS1-regulated site on the OPN promoter, using luciferase reporter assays of the promoter deletions, identified a novel NF-kappaB site (OPN/NF-kappaB). Electrophoretic mobility shift assays and chromatin immunoprecipitations (ChIP) confirmed this site to be an NF-kappaB-binding site. We also show a role of HDAC3 in suppression of OPN via OPN/NF-kappaB.

Conclusion: Our results show that BRMS1 regulates OPN transcription by abrogating NF-kappaB activation. Thus, we identify OPN, a tumor-metastasis activator, as a crucial downstream target of BRMS1. Suppression of OPN may be one of the possible underlying mechanisms of BRMS1-dependent suppression of tumor metastasis.

Publication types

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

MeSH terms

  • Acetylation
  • Binding Sites
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Female
  • Histone Deacetylases / metabolism
  • Humans
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Neoplasm Proteins
  • Osteopontin / genetics*
  • Promoter Regions, Genetic
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Repressor Proteins
  • Transcription Factor RelA / metabolism
  • Transcription, Genetic*
  • Transfection

Substances

  • BRMS1 protein, human
  • NF-kappa B
  • Neoplasm Proteins
  • Recombinant Proteins
  • Repressor Proteins
  • Transcription Factor RelA
  • Osteopontin
  • Histone Deacetylases
  • histone deacetylase 3