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

Abstract

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.

• Authors: Kasper Almholt, Boye S Nielsen, Thomas L Frandsen, Nils Brünner, Keld Danø, Morten Johnsen
• Journal: Oncogene (Oncogene) Vol. 22 Issue 28 Pg. 4389-97 (Jul 10 2003) ISSN: 0950-9232 [Print] England
• PMID: 12853975 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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