FGF-1-induced matrix metalloproteinase-9 expression in breast cancer cells is mediated by increased activities of NF-kappaB and activating protein-1

Mol Carcinog. 2008 Jun;47(6):424-35. doi: 10.1002/mc.20398.


Matrix metalloproteinase-9 (MMP-9) plays a critical role in tumor invasion and metastasis. Here, we investigate the effect of fibroblast growth factor-1 (FGF-1) on the expression of MMP-9 in ENU1564, an ethyl-N-nitrosourea-induced rat mammary adenocarcinoma cell line. We observed that FGF-1 induces a dose-dependent increase in MMP-9 mRNA, protein, and activity in ENU1564 cells. To gain insight into the molecular mechanism of MMP-9 regulation by FGF-1, we investigated the role of components of PI3K-Akt and MEK1/2-ERK signaling pathways in our system since NF-kappaB and AP-1 transcription factor binding sites have been characterized in the upstream region of the MMP-9 gene. We demonstrated that FGF-1 increases Akt phosphorylation, triggers nuclear translocation of NF-kappaBp65, and enhances degradation of cytoplasmic IkappaBalpha. Pretreatment of cells with LY294002, a PI3K inhibitor, significantly inhibited MMP-9 protein expression in FGF-1-treated cells. Conversely, our data show that FGF-1 increases ERK phosphorylation in ENU1564 cells, increases c-jun and c-fos mRNA expression in a time-dependent manner, and triggers nuclear translocation of c-jun. Pretreatment of cells with PD98059, a MEK1/2 inhibitor significantly inhibited MMP-9 protein expression in FGF-1 treated cells. Finally, we observed increased DNA binding of NF-kappaB and AP-1 in FGF-1-treated cells and that mutation of either NF-kappaB or AP-1 response elements prevented MMP-9 promoter activation by FGF-1. Taken together, these results demonstrated that FGF-1-induced MMP-9 expression in ENU1564 cells is associated with increasing DNA binding activities of NF-kappaB and AP-1 and involve activation of a dual signaling pathway, PI3K-Akt and MEK1/2-ERK.

MeSH terms

  • Animals
  • Base Sequence
  • Blotting, Western
  • Carcinogens / toxicity
  • Cell Line, Tumor
  • Chromones / pharmacology
  • Cloning, Molecular
  • DNA Primers
  • Ethylnitrosourea / toxicity
  • Female
  • Fibroblast Growth Factor 1 / pharmacology*
  • Flavonoids / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, fos
  • Genes, jun
  • Mammary Neoplasms, Experimental / chemically induced
  • Mammary Neoplasms, Experimental / enzymology*
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Morpholines / pharmacology
  • NF-kappa B / metabolism*
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factor AP-1 / metabolism*


  • Carcinogens
  • Chromones
  • DNA Primers
  • Flavonoids
  • Morpholines
  • NF-kappa B
  • Transcription Factor AP-1
  • Fibroblast Growth Factor 1
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Matrix Metalloproteinase 9
  • Ethylnitrosourea
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one