The 2G single nucleotide polymorphism (SNP) in the MMP-1 promoter contributes to high levels of MMP-1 transcription in MCF-7/ADR breast cancer cells

Breast Cancer Res Treat. 2003 Nov;82(2):75-82. doi: 10.1023/B:BREA.0000003948.14026.7c.


Degradation of stromal collagens in the extracellular matrix is mediated largely by matrix metalloproteinase-1 (MMP-1; collagenase-1), and high constitutive levels of MMP-1 in breast cancer correlate with a poor prognosis and invasive disease. MMP-1 expression is, in part, controlled by the mitogen-activated protein kinase (MAPK) pathway(s), which may target several activator protein-1 (AP-1) and polyoma enhancing activity-3/E26 virus (PEA3/ETS) sites within the promoter. An additional ETS site in the MMP-1 promoter is conferred by a single nucleotide polymorphism (SNP) at -1607 bp, when two guanines (5'-GGAT-3'; '2G allele/SNP') are present instead of one guanine (5'-GAT-3'; '1G allele/SNP'). This SNP is adjacent to an AP-1 site at -1602 bp, and in the presence of the 2G allele (ETS site), these sites cooperate to induce higher levels of transcription. ERK 1/2 is one component of the MAPK pathway and is constitutively active in MCF-7/ADR breast cancer cells, which are 1G/2G heterozygotes. This study demonstrates that when these cells are treated with PD098059, an ERK-specific inhibitor, MMP-1 mRNA levels are significantly decreased, suggesting that high constitutive expression of MMP-1 in these cells results from continuous ERK 1/2 activation. Using transient transfection, we determined that this signaling pathway targets different AP-1/ETS sites, depending upon which allele is present. Furthermore, in these cells, the AP-1 site at -1602 bp enhances transcription in the presence of the 2G SNP, but represses transcription from the 1G SNP. Finally, inhibiting ERK signaling and MMP-1 expression blocks type I collagen degradation and reduces the invasive ability of the MCF-7/ADR cells. We conclude that ERK 1/2 signaling and the 2G SNP mediate high levels of MMP-1 expression, which may contribute to the invasive potential of these breast cancer cells.

Publication types

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

MeSH terms

  • Binding Sites / genetics
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / metabolism
  • Collagen Type I / metabolism
  • Down-Regulation
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Humans
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Matrix Metalloproteinase 1 / genetics*
  • Matrix Metalloproteinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic / genetics*
  • Pyridines / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcription Factor AP-1 / metabolism
  • Transcription, Genetic
  • Transfection


  • Collagen Type I
  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Pyridines
  • RNA, Messenger
  • Transcription Factor AP-1
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 1
  • SB 203580
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one