Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation

Oncogene. 2006 Apr 13;25(16):2379-92. doi: 10.1038/sj.onc.1209273.


The process of cancer cell invasion involves degradation of the extracellular matrix (ECM) by proteases, integrin adhesion and cell motility. The role of ECM degrading proteases on the hypoxia-induced invasion of breast carcinoma cells was investigated. Hypoxia markedly increased the invasion capacity of MDA-MB-231 and MDA-MB-435 breast carcinoma cell lines. Matrix metalloproteinase (MMP) inhibitors blocked the hypoxia-induced invasion, whereas other protease inhibitors had no effect. Antibodies or siRNAs blocking either membrane type-1 MMP (MT1-MMP) or MMP-2 were effective in reducing the hypoxia-induced invasion. Serum-free reconstitution experiments confirmed the involvement of the MT1-MMP/MMP-2/tissue inhibitor of metalloproteinase-2 complex in this hypoxia-induced response. Overexpression of MT1-MMP in a poorly invasive breast cancer cell line, T47-D, promoted hypoxia-induced invasion and MMP-2 activation. Cell surface accumulation and activation of MT1-MMP without apparent regulation at the mRNA or protein levels indicated a post-translational adaptive response to hypoxia. Inhibition of the small GTPase RhoA eliminated the hypoxia-induced invasion and blocked the localization of MT1-MMP to the plasma membrane. Zymographic and molecular analysis of human breast tumors showed a strong correlation between hypoxic microenvironments and MMP-2 activation without changes in MT1-MMP expression. Our studies suggest that hypoxic tumor microenvironments promote breast cancer invasion through an MT1-MMP-dependent mechanism.

Publication types

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

MeSH terms

  • Breast Neoplasms / pathology*
  • Cell Hypoxia*
  • Cell Line, Tumor
  • Enzyme Activation
  • Female
  • Humans
  • Matrix Metalloproteinase 2 / physiology*
  • Matrix Metalloproteinases / physiology*
  • Matrix Metalloproteinases, Membrane-Associated
  • Neoplasm Invasiveness
  • RNA Interference
  • RNA, Messenger / analysis
  • Tissue Inhibitor of Metalloproteinase-2 / physiology
  • rhoA GTP-Binding Protein / physiology


  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-2
  • Matrix Metalloproteinases
  • Matrix Metalloproteinases, Membrane-Associated
  • Matrix Metalloproteinase 2
  • rhoA GTP-Binding Protein