Metastasis of transgenic breast cancer in plasminogen activator inhibitor-1 gene-deficient mice

Oncogene. 2003 Jul 10;22(28):4389-97. doi: 10.1038/sj.onc.1206601.


The plasminogen activator inhibitor-1 (PAI-1) blocks the activation of plasmin(ogen), an extracellular protease vital to cancer invasion. PAI-1 is like the corresponding plasminogen activator uPA (urokinase-type plasminogen activator) consistently expressed in human breast cancer. Paradoxically, high levels of PAI-1 as well as uPA are equally associated with poor prognosis in cancer patients. PAI-1 is thought to play a vital role for the controlled extracellular proteolysis during tumor neovascularization. We have studied the effect of PAI-1 deficiency in a transgenic mouse model of metastasizing breast cancer. In these tumors, the expression pattern of uPA and PAI-1 resembles that of human ductal breast cancer and plasminogen is required for efficient metastasis. In a cohort of 63 transgenic mice that were either PAI-1-deficient or wild-type sibling controls, primary tumor growth and vascular density were unaffected by PAI-1 status. PAI-1 deficiency also did not significantly affect the lung metastatic burden. These results agree with the virtual lack of spontaneous phenotype in PAI-1-deficient mice and humans and may reflect that the plasminogen activation reaction is not rate limiting for tumor vascularization and metastasis, or that there is a functional redundancy between PAI-1 and other inhibitors of the uPA/plasmin system, masking the effect of PAI-1 deficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Lung Neoplasms / secondary
  • Male
  • Mammary Neoplasms, Experimental / blood supply*
  • Mammary Neoplasms, Experimental / pathology*
  • Mammary Tumor Virus, Mouse
  • Mice
  • Mice, Transgenic
  • Neovascularization, Pathologic / etiology*
  • Neovascularization, Pathologic / prevention & control
  • Plasminogen Activator Inhibitor 1 / deficiency
  • Plasminogen Activator Inhibitor 1 / physiology*
  • Plasminogen Activator Inhibitor 2 / analysis
  • Urokinase-Type Plasminogen Activator / analysis


  • Plasminogen Activator Inhibitor 1
  • Plasminogen Activator Inhibitor 2
  • Urokinase-Type Plasminogen Activator