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.
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Abbreviations
- GAPDH:
-
glyceraldehyde-3-phosphate dehydrogenase
- H&E:
-
hematoxylin and eosin
- MMTV:
-
mouse mammary tumor virus
- PA:
-
plasminogen activation
- PAI:
-
plasminogen activator inhibitor
- PBS:
-
phosphate-buffered saline
- PymT:
-
polyomavirus middle T antigen
- tPA:
-
tissue-type plasminogen activator
- uPA:
-
urokinase-type plasminogen activator
- uPAR:
-
urokinase-type plasminogen activator receptor
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Acknowledgements
We are indebted to Drs William J Muller and Peter Carmeliet for generously providing us with the MMTV-PymT and the PAI-1-deficient mice, respectively. We thank Agnieszka Ingvorsen, Pia Pedersen, Dorthe S. Olsen, Maria K. Kiersgaard and Mette M Lungholt for expert technical assistance, John Post for the photographic reproductions and Ib J Christensen for assistance with the statistical analyses. This work was supported by grants from Søren and Helene Hempels Foundation, Krista and Viggo Petersens Foundation, the Danish Research Agency and the Copenhagen Hospital Corporation.
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Almholt, K., Nielsen, B., Frandsen, T. et al. Metastasis of transgenic breast cancer in plasminogen activator inhibitor-1 gene-deficient mice. Oncogene 22, 4389–4397 (2003). https://doi.org/10.1038/sj.onc.1206601
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DOI: https://doi.org/10.1038/sj.onc.1206601
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