Epidermal growth factor and amphiregulin up-regulate matrix metalloproteinase-9 (MMP-9) in human breast cancer cells

Int J Cancer. 1997 Mar 17;70(6):722-6. doi: 10.1002/(sici)1097-0215(19970317)70:6<722::aid-ijc15>3.0.co;2-b.


The EGF family of proteins encompasses several polypeptides such as epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), amphiregulin (AR) and heregulin (HRG-beta 1). These polypeptides regulate proliferation in breast cancer cells through interaction with membrane receptors. It has been previously shown that high EGF receptor number correlates with aggressive behavior and increased metastasis in human breast cancer. In the present study, we investigated the association between EGF and EGF-like ligand-induced DNA synthesis and secretion of MMP-9 and MMP-2 in metastatic SKBR-3 and non-metastatic MCF-7 breast cancer cells. Exposure of SKBR-3 cells to EGF or AR induces expression of MMP-9 but has no effect on MMP-2 secretion. In contrast to EGF and AR, HRG had no effect on gelatinase induction. None of the EGF polypeptides had any effect on gelatinase induction in MCF-7 non-metastatic breast cancer cells. While a relatively specific inhibitor of EGF receptor tyrosine kinase, PD 153035, inhibited EGF-, AR- and HRG-induced cell proliferation, it had no effect on MMP-9 induced by EGF and AR. Experimental evidence suggests that signaling mechanisms for cell proliferation and MMP-9 induction are mediated by different pathways down-stream of EGF receptor autophosphorylation or that low levels of EGF-induced signal that escape inhibition are sufficient to induce MMP-9 but unable to support cell proliferation. In addition, our results suggest that EGF and AR may modulate invasion of metastatic breast cancer cells by increasing the expression of MMPs.

MeSH terms

  • Amphiregulin
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / pathology*
  • Cell Division / drug effects
  • Cell Division / physiology
  • Collagenases / biosynthesis
  • Collagenases / metabolism*
  • EGF Family of Proteins
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / pharmacology*
  • ErbB Receptors / antagonists & inhibitors
  • Gelatinases / metabolism
  • Glycoproteins / pharmacology*
  • Growth Substances / pharmacology*
  • Humans
  • Intercellular Signaling Peptides and Proteins*
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Metalloendopeptidases / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Quinazolines / pharmacology
  • Tumor Cells, Cultured
  • Up-Regulation / drug effects


  • AREG protein, human
  • Amphiregulin
  • Antineoplastic Agents
  • EGF Family of Proteins
  • Enzyme Inhibitors
  • Glycoproteins
  • Growth Substances
  • Intercellular Signaling Peptides and Proteins
  • Quinazolines
  • Epidermal Growth Factor
  • ErbB Receptors
  • Collagenases
  • Gelatinases
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • 4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline