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. 1994 Feb;69(2):398–405. doi: 10.1038/bjc.1994.74

Prognostic value of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in breast carcinomas.

C Bouchet 1, F Spyratos 1, P M Martin 1, K Hacène 1, A Gentile 1, J Oglobine 1
PMCID: PMC1968685  PMID: 8297742

Abstract

It is now clearly established that proteolytic enzymes, including plasminogen activator (uPA), play an important role in breaking down the extracellular matrix, which is considered to be a step in metastasis formation. Plasminogen activators are controlled at various levels. Two inhibitors, PAI-1 and PAI-2, have been identified, the latter being more specific for uPA. In attempts to determine their prognostic value, it is essential to investigate the relative importance of these parameters and their interactions. We used an immunoenzymatic method to assay uPA, PAI-1 and PAI-2 antigens in cytosols prepared from 314 primary breast tumours. The patients were followed up for a minimum of 6 years and all relevant clinical and laboratory findings were recorded. Univariate analysis confirmed the poor outcome of patients whose tumours contained large amounts of uPA and PAI-1. In addition, low levels of PAI-2 correlated with shorter disease-free survival in the overall population (P = 0.02), post-menopausal women (P = 0.02) and women without lymph node involvement (P = 0.02). Multivariate analysis in the 'main effects' Cox model identified node involvement, macroscopic tumour size and PAI-2 as significant variables. The 'interactive' model, taking into account interactions between uPA and its two inhibitors, identified a first subgroup with a very poor prognosis associating either high levels of PAI-1 with low levels of PAI-2 in the overall population and the women with no node involvement or high levels of uPA with low levels of PAI-2 in the group of menopausal women. We conclude that PAI-1 provides the same prognostic information as uPA, and does not appear to play a role as an inhibitor. In contrast, PAI-2 increases the prognostic value of uPA, particularly in post-menopausal women, and PAI-1 in patients with no node involvement.

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Selected References

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  1. BLOOM H. J., RICHARDSON W. W. Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer. 1957 Sep;11(3):359–377. doi: 10.1038/bjc.1957.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  3. Cubellis M. V., Wun T. C., Blasi F. Receptor-mediated internalization and degradation of urokinase is caused by its specific inhibitor PAI-1. EMBO J. 1990 Apr;9(4):1079–1085. doi: 10.1002/j.1460-2075.1990.tb08213.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Danø K., Andreasen P. A., Grøndahl-Hansen J., Kristensen P., Nielsen L. S., Skriver L. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res. 1985;44:139–266. doi: 10.1016/s0065-230x(08)60028-7. [DOI] [PubMed] [Google Scholar]
  5. Duffy M. J. Do proteases play a role in cancer invasion and metastasis? Eur J Cancer Clin Oncol. 1987 May;23(5):583–589. doi: 10.1016/0277-5379(87)90326-9. [DOI] [PubMed] [Google Scholar]
  6. Duffy M. J., Reilly D., O'Sullivan C., O'Higgins N., Fennelly J. J., Andreasen P. Urokinase-plasminogen activator, a new and independent prognostic marker in breast cancer. Cancer Res. 1990 Nov 1;50(21):6827–6829. [PubMed] [Google Scholar]
  7. Foekens J. A., Schmitt M., van Putten W. L., Peters H. A., Bontenbal M., Jänicke F., Klijn J. G. Prognostic value of urokinase-type plasminogen activator in 671 primary breast cancer patients. Cancer Res. 1992 Nov 1;52(21):6101–6105. [PubMed] [Google Scholar]
  8. Foucré D., Bouchet C., Hacène K., Pourreau-Schneider N., Gentile A., Martin P. M., Desplaces A., Oglobine J. Relationship between cathepsin D, urokinase, and plasminogen activator inhibitors in malignant vs benign breast tumours. Br J Cancer. 1991 Nov;64(5):926–932. doi: 10.1038/bjc.1991.428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hollas W., Blasi F., Boyd D. Role of the urokinase receptor in facilitating extracellular matrix invasion by cultured colon cancer. Cancer Res. 1991 Jul 15;51(14):3690–3695. [PubMed] [Google Scholar]
  10. Jänicke F., Schmitt M., Graeff H. Clinical relevance of the urokinase-type and tissue-type plasminogen activators and of their type 1 inhibitor in breast cancer. Semin Thromb Hemost. 1991 Jul;17(3):303–312. doi: 10.1055/s-2007-1002624. [DOI] [PubMed] [Google Scholar]
  11. Jänicke F., Schmitt M., Pache L., Ulm K., Harbeck N., Höfler H., Graeff H. Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat. 1993;24(3):195–208. doi: 10.1007/BF01833260. [DOI] [PubMed] [Google Scholar]
  12. Kruithof E. K., Gudinchet A., Bachmann F. Plasminogen activator inhibitor 1 and plasminogen activator inhibitor 2 in various disease states. Thromb Haemost. 1988 Feb 25;59(1):7–12. [PubMed] [Google Scholar]
  13. Lawless J. F., Singhal K. ISMOD: an all-subsets regression program for generalized linear models. I. Statistical and computational background. Comput Methods Programs Biomed. 1987 Apr;24(2):117–124. doi: 10.1016/0169-2607(87)90022-8. [DOI] [PubMed] [Google Scholar]
  14. Lawless J. F., Singhal K. ISMOD: an all-subsets regression program for generalized linear models. II. Program guide and examples. Comput Methods Programs Biomed. 1987 Apr;24(2):125–134. doi: 10.1016/0169-2607(87)90023-x. [DOI] [PubMed] [Google Scholar]
  15. Loskutoff D. J., Edgington T. E. Synthesis of a fibrinolytic activator and inhibitor by endothelial cells. Proc Natl Acad Sci U S A. 1977 Sep;74(9):3903–3907. doi: 10.1073/pnas.74.9.3903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Markus G. The relevance of plasminogen activators to neoplastic growth. A review of recent literature. Enzyme. 1988;40(2-3):158–172. doi: 10.1159/000469158. [DOI] [PubMed] [Google Scholar]
  17. McGuire W. L. Breast cancer prognostic factors: evaluation guidelines. J Natl Cancer Inst. 1991 Feb 6;83(3):154–155. doi: 10.1093/jnci/83.3.154. [DOI] [PubMed] [Google Scholar]
  18. Pyke C., Kristensen P., Ralfkiaer E., Eriksen J., Danø K. The plasminogen activation system in human colon cancer: messenger RNA for the inhibitor PAI-1 is located in endothelial cells in the tumor stroma. Cancer Res. 1991 Aug 1;51(15):4067–4071. [PubMed] [Google Scholar]
  19. Pyke C., Kristensen P., Ralfkiaer E., Grøndahl-Hansen J., Eriksen J., Blasi F., Danø K. Urokinase-type plasminogen activator is expressed in stromal cells and its receptor in cancer cells at invasive foci in human colon adenocarcinomas. Am J Pathol. 1991 May;138(5):1059–1067. [PMC free article] [PubMed] [Google Scholar]
  20. Quax P. H., van Leeuwen R. T., Verspaget H. W., Verheijen J. H. Protein and messenger RNA levels of plasminogen activators and inhibitors analyzed in 22 human tumor cell lines. Cancer Res. 1990 Mar 1;50(5):1488–1494. [PubMed] [Google Scholar]
  21. Reilly D., Christensen L., Duch M., Nolan N., Duffy M. J., Andreasen P. A. Type-1 plasminogen activator inhibitor in human breast carcinomas. Int J Cancer. 1992 Jan 21;50(2):208–214. doi: 10.1002/ijc.2910500209. [DOI] [PubMed] [Google Scholar]
  22. Sappino A. P., Busso N., Belin D., Vassalli J. D. Increase of urokinase-type plasminogen activator gene expression in human lung and breast carcinomas. Cancer Res. 1987 Aug 1;47(15):4043–4046. [PubMed] [Google Scholar]
  23. Schmitt M., Goretzki L., Jänicke F., Calvete J., Eulitz M., Kobayashi H., Chucholowski N., Graeff H. Biological and clinical relevance of the urokinase-type plasminogen activator (uPA) in breast cancer. Biomed Biochim Acta. 1991;50(4-6):731–741. [PubMed] [Google Scholar]
  24. Spyratos F., Martin P. M., Hacène K., Romain S., Andrieu C., Ferrero-Poüs M., Deytieux S., Le Doussal V., Tubiana-Hulin M., Brunet M. Multiparametric prognostic evaluation of biological factors in primary breast cancer. J Natl Cancer Inst. 1992 Aug 19;84(16):1266–1272. doi: 10.1093/jnci/84.16.1266. [DOI] [PubMed] [Google Scholar]
  25. Sumiyoshi K., Serizawa K., Urano T., Takada Y., Takada A., Baba S. Plasminogen activator system in human breast cancer. Int J Cancer. 1992 Feb 1;50(3):345–348. doi: 10.1002/ijc.2910500303. [DOI] [PubMed] [Google Scholar]
  26. Tanaka N., Fukao H., Ueshima S., Okada K., Yasutomi M., Matsuo O. Plasminogen activator inhibitor 1 in human carcinoma tissues. Int J Cancer. 1991 Jun 19;48(4):481–484. doi: 10.1002/ijc.2910480402. [DOI] [PubMed] [Google Scholar]
  27. de Bruin P. A., Griffioen G., Verspaget H. W., Verheijen J. H., Lamers C. B. Plasminogen activators and tumor development in the human colon: activity levels in normal mucosa, adenomatous polyps, and adenocarcinomas. Cancer Res. 1987 Sep 1;47(17):4654–4657. [PubMed] [Google Scholar]

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