Transcriptional repression of the human collagenase-1 (MMP-1) gene in MDA231 breast cancer cells by all-trans-retinoic acid requires distal regions of the promoter

Br J Cancer. 1999 Jan;79(2):221-8. doi: 10.1038/sj.bjc.6690037.

Abstract

In the present study, we investigated the mechanisms controlling constitutive transcription of collagenase-1 and its repression by all-trans-retinoic acid (RA) in the highly invasive metastatic and oestrogen-receptor-negative breast cancer cell line MDA231. A combination of in vivo and in vitro experiments that include DNAase I hypersensitivity assays, transient transfection of collagenase-1 promoter constructs, and electrophoretic mobility shift assays implicate several PEA3 sites, binding sites for Ets-related transcription factors, in the constitutive expression of the human collagenase-1 promoter. Transient transfection of promoter constructs linked to the luciferase reporter, along with gel retardation assays, revealed that repression of collagenase-1 transcription by RA is not dependent on the proximal AP-1 site, but, rather, requires sequences located in distal regions of the promoter. Transcriptional analyses and electrophoretic mobility shift assays suggest that the PEA3 site located at -3108 bp facilitates, at least in part, the transcriptional repression of the human collagenase-1 gene in MDA231 cells. We conclude that collagenase-1 repression in MDA231 cells occurs by a novel regulatory pathway that does not depend on the proximal AP-1 site at -73 bp, but does depend on distal regions in the collagenase-1 promoter.

Publication types

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

MeSH terms

  • Collagenases / biosynthesis*
  • Collagenases / genetics
  • Deoxyribonuclease I / pharmacology
  • Enzyme Repression / genetics
  • Female
  • Gene Expression / drug effects
  • Humans
  • Matrix Metalloproteinase 1
  • Matrix Metalloproteinase Inhibitors
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • Promoter Regions, Genetic
  • Receptors, Retinoic Acid / drug effects*
  • Receptors, Retinoic Acid / metabolism
  • Retinoic Acid Receptor alpha
  • Transcription, Genetic / drug effects*
  • Transfection
  • Tretinoin / pharmacology*
  • Tumor Cells, Cultured / drug effects

Substances

  • Matrix Metalloproteinase Inhibitors
  • Neoplasm Proteins
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • retinoic acid receptor beta
  • retinoic acid receptor gamma
  • Tretinoin
  • Deoxyribonuclease I
  • Collagenases
  • Matrix Metalloproteinase 1