This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grøndahl-Hansen, J. Articles by Blichert-Toft, M. Search for Related Content PubMed PubMed Citation Articles by Grøndahl-Hansen, J. Articles by Blichert-Toft, M.

High Levels of Urokinase-type Plasminogen Activator and Its Inhibitor PAI-1 in Cytosolic Extracts of Breast Carcinomas Are Associated with Poor Prognosis¹

Finsen Laboratory, Rigshospitalet, Copenhagen [J. G-H., I. J. C., N. B., K. D.]; Department of Biochemistry and Nutrition, Technical University of Denmark, Lyngby [J. G-H., C. R.]; and Danish Breast Cancer Cooperative Group, Copenhagen [H. T. M., M. B-T.], Denmark

The urokinase pathway of plasminogen activation is supposed to be involved in proteolytic degradation of the extracellular matrix during cancer invasion. The prognostic value of urokinase-type plasminogen activator (uPA) and type 1 plasminogen activator inhibitor (PAI-1) levels in cytosolic extracts of ductal breast carcinomas was studied, retrospectively, in 118 premenopausal and 72 postmenopausal high-risk patients entered into the protocol of Danish Breast Cancer Cooperative Group trials for adjuvant treatment of breast cancer. The median observation time was 8.5 years. uPA and PAI-1 levels were determined by sandwich enzyme-linked immunosorbent assays. There is a strong correlation between these levels (P < 0.001; r = 0.57). Univariate analysis showed that a high uPA level is significantly associated with short overall survival in both premenopausal (P < 0.001) and postmenopausal (P = 0.03) patients, while a high PAI-1 content significantly predicts shorter overall survival in premenopausal (P = 0.005) and postmenopausal (P < 0.001) patients and shorter relapse-free survival in postmenopausal patients (P < 0.001). When the levels of uPA and PAI-1 are related to those of other prognostic parameters, both high uPA and high PAI-1 levels are associated with grade of anaplasia in premenopausal patients and with number of tumor-positive lymph nodes in postmenopausal patients. A high PAI-1 level is associated with low estrogen and progesterone receptor levels in both pre- and postmenopausal patients. The prognostic value of uPA and PAI-1 levels was compared with that of established prognostic parameters by multivariate analysis. In premenopausal patients, high uPA is an independent prognostic parameter for shorter overall survival, the relative risk being 2.0 (95% confidence interval, 1.1–3.7). In postmenopausal patients, a high PAI-1 level is a strong and independent factor in predicting shorter overall survival with a relative risk of 2.9 (95% confidence interval, 1.5–5.8). In this group of patients a high PAI-1 level is also an independent predictor of shorter relapse-free survival (relative risk, 2.1; 95% confidence interval, 1.1–3.9). These data together with previous reports indicate that uPA and PAI-1 are potentially important prognostic factors in breast cancer. This is in good agreement with the supposed function of uPA in cancer invasion. It is proposed that PAI-1 plays a role in protecting the tumor against degrading itself. Alternatively, the PAI-1 level may be a biochemical marker of tumor angiogenesis.

¹ Supported by the Danish Medical Research Council, the Danish Cancer Society, and the NOVO Foundation.

² To whom requests for reprints should be addressed, at Finsen Laboratory, Rigshospitalet, Strandboulevarden 49, DK-2100 Copenhagen, ØDenmark.

Received 11/ 3/92. Accepted 3/29/93.

This article has been cited by other articles:

				T. C. Hurd, S. Sait, S. Kohga, J. Winston, M. Martinick, R. Saxena, H. Lankes, G. Markus, S. Harvey, and J. F. Gibbs Plasminogen Activator System Localization in 60 Cases of Ductal Carcinoma In Situ Ann. Surg. Oncol., November 1, 2007; 14(11): 3117 - 3124. [Abstract] [Full Text] [PDF]

				B.-Y. Bao, S.-D. Yeh, and Y.-F. Lee 1{alpha},25-dihydroxyvitamin D3 inhibits prostate cancer cell invasion via modulation of selective proteases Carcinogenesis, January 1, 2006; 27(1): 32 - 42. [Abstract] [Full Text] [PDF]

				M. Cicek, R. Fukuyama, D. R. Welch, N. Sizemore, and G. Casey Breast Cancer Metastasis Suppressor 1 Inhibits Gene Expression by Targeting Nuclear Factor-{kappa}B Activity Cancer Res., May 1, 2005; 65(9): 3586 - 3595. [Abstract] [Full Text] [PDF]

				N. Bonafe, M. Gilmore-Hebert, N. L. Folk, M. Azodi, Y. Zhou, and S. K. Chambers Glyceraldehyde-3-Phosphate Dehydrogenase Binds to the AU-Rich 3' Untranslated Region of Colony-Stimulating Factor-1 (CSF-1) Messenger RNA in Human Ovarian Cancer Cells: Possible Role in CSF-1 Posttranscriptional Regulation and Tumor Phenotype Cancer Res., May 1, 2005; 65(9): 3762 - 3771. [Abstract] [Full Text] [PDF]

				K. Yamamoto, K. Takeshita, T. Kojima, J. Takamatsu, and H. Saito Aging and plasminogen activator inhibitor-1 (PAI-1) regulation: implication in the pathogenesis of thrombotic disorders in the elderly Cardiovasc Res, May 1, 2005; 66(2): 276 - 285. [Abstract] [Full Text] [PDF]

				M Lacroix, R-A Toillon, and G Leclercq Stable 'portrait' of breast tumors during progression: data from biology, pathology and genetics Endocr. Relat. Cancer, September 1, 2004; 11(3): 497 - 522. [Abstract] [Full Text] [PDF]

				A. Paju, J. Vartiainen, C. Haglund, O. Itkonen, K. von Boguslawski, A. Leminen, T. Wahlstrom, and U.-H. Stenman Expression of Trypsinogen-1, Trypsinogen-2, and Tumor-Associated Trypsin Inhibitor in Ovarian Cancer: Prognostic Study on Tissue and Serum Clin. Cancer Res., July 15, 2004; 10(14): 4761 - 4768. [Abstract] [Full Text] [PDF]

				H. T. Mouridsen and N. Brunner Clinical Infrastructures to Support Proteomic Studies of Tissue and Fluids in Breast Cancer Mol. Cell. Proteomics, April 1, 2004; 3(4): 302 - 310. [Abstract] [Full Text] [PDF]

				T. Sakakibara, K. Hibi, Y. Kodera, K. Ito, S. Akiyama, and A. Nakao Plasminogen Activator Inhibitor-1 as a Potential Marker for the Malignancy of Esophageal Squamous Cell Carcinoma Clin. Cancer Res., February 15, 2004; 10(4): 1375 - 1378. [Abstract] [Full Text] [PDF]

				C. Parr, G. Watkins, R. E. Mansel, and W. G. Jiang The Hepatocyte Growth Factor Regulatory Factors in Human Breast Cancer Clin. Cancer Res., January 1, 2004; 10(1): 202 - 211. [Abstract] [Full Text] [PDF]

				B. V. Offersen, B. S. Nielsen, G. Hoyer-Hansen, F. Rank, S. Hamilton-Dutoit, J. Overgaard, and P. A. Andreasen The Myofibroblast Is the Predominant Plasminogen Activator Inhibitor-1-Expressing Cell Type in Human Breast Carcinomas Am. J. Pathol., November 1, 2003; 163(5): 1887 - 1899. [Abstract] [Full Text] [PDF]

				S. Stefansson and D. A. Lawrence Old Dogs and New Tricks, Proteases, Inhibitors, and Cell Migration Sci. Signal., July 1, 2003; 2003(189): pe24 - pe24. [Abstract] [Full Text] [PDF]

				N. Devoogdt, G. Hassanzadeh Ghassabeh, J. Zhang, L. Brys, P. De Baetselier, and H. Revets Secretory leukocyte protease inhibitor promotes the tumorigenic and metastatic potential of cancer cells PNAS, May 13, 2003; 100(10): 5778 - 5782. [Abstract] [Full Text] [PDF]

				S. Shetty, K. Bdeir, D. B. Cines, and S. Idell Induction of Plasminogen Activator Inhibitor-1 by Urokinase in Lung Epithelial Cells J. Biol. Chem., May 9, 2003; 278(20): 18124 - 18131. [Abstract] [Full Text] [PDF]

				T. Utsunomiya, Y. Hara, A. Kataoka, M. Morita, H. Arakawa, M. Mori, and S. Nishimura Cystatin-like Metastasis-associated Protein mRNA Expression in Human Colorectal Cancer Is Associated with Both Liver Metastasis and Patient Survival Clin. Cancer Res., August 1, 2002; 8(8): 2591 - 2594. [Abstract] [Full Text] [PDF]

				R. Riisbro, I. J. Christensen, T. Piironen, M. Greenall, B. Larsen, R. W. Stephens, C. Han, G. Hoyer-Hansen, K. Smith, N. Brunner, et al. Prognostic Significance of Soluble Urokinase Plasminogen Activator Receptor in Serum and Cytosol of Tumor Tissue from Patients with Primary Breast Cancer Clin. Cancer Res., May 1, 2002; 8(5): 1132 - 1141. [Abstract] [Full Text] [PDF]

				N. Harbeck, R. E. Kates, and M. Schmitt Clinical Relevance of Invasion Factors Urokinase-Type Plasminogen Activator and Plasminogen Activator Inhibitor Type 1 for Individualized Therapy Decisions in Primary Breast Cancer Is Greatest When Used in Combination J. Clin. Oncol., February 15, 2002; 20(4): 1000 - 1007. [Abstract] [Full Text] [PDF]

				M. P. Look, W. L. J. van Putten, M. J. Duffy, N. Harbeck, I. J. Christensen, C. Thomssen, R. Kates, F. Spyratos, M. Ferno, S. Eppenberger-Castori, et al. Pooled Analysis of Prognostic Impact of Urokinase-Type Plasminogen Activator and Its Inhibitor PAI-1 in 8377 Breast Cancer Patients J Natl Cancer Inst, January 16, 2002; 94(2): 116 - 128. [Abstract] [Full Text] [PDF]

				B. S. Nielsen, F. Rank, J. M. Lopez, M. Balbin, F. Vizoso, L. R. Lund, K. Dano, and C. Lopez-Otin Collagenase-3 Expression in Breast Myofibroblasts as a Molecular Marker of Transition of Ductal Carcinoma in Situ Lesions to Invasive Ductal Carcinomas Cancer Res., October 1, 2001; 61(19): 7091 - 7100. [Abstract] [Full Text] [PDF]

				V. C. L. Lin, A. S. Eng, N. E. Hen, E. H. L. Ng, and S. H. Chowdhury Effect of Progesterone on the Invasive Properties and Tumor Growth of Progesterone Receptor-transfected Breast Cancer Cells MDA-MB-231 Clin. Cancer Res., September 1, 2001; 7(9): 2880 - 2886. [Abstract] [Full Text] [PDF]

				P. O. Chappuis, B. Dieterich, V. Sciretta, C. Lohse, H. Bonnefoi, S. Remadi, and A.-P. Sappino Functional Evaluation of Plasmin Formation in Primary Breast Cancer J. Clin. Oncol., May 15, 2001; 19(10): 2731 - 2738. [Abstract] [Full Text] [PDF]

				A. Samoylenko, U. Roth, K. Jungermann, and T. Kietzmann The upstream stimulatory factor-2a inhibits plasminogen activator inhibitor-1 gene expression by binding to a promoter element adjacent to the hypoxia-inducible factor-1 binding site Blood, May 1, 2001; 97(9): 2657 - 2666. [Abstract] [Full Text] [PDF]

				P. Malmstrom, P-O. Bendahl, P. Boiesen, N. Brunner, I. Idvall, and M. Ferno S-Phase Fraction and Urokinase Plasminogen Activator Are Better Markers for Distant Recurrences Than Nottingham Prognostic Index and Histologic Grade in a Prospective Study of Premenopausal Lymph Node-Negative Breast Cancer J. Clin. Oncol., April 1, 2001; 19(7): 2010 - 2019. [Abstract] [Full Text] [PDF]

				S. M. Smorenburg and C. J. F. Van Noorden The Complex Effects of Heparins on Cancer Progression and Metastasis in Experimental Studies Pharmacol. Rev., March 1, 2001; 53(1): 93 - 106. [Abstract] [Full Text] [PDF]

				A. N. Pedersen, I. J. Christensen, R. W. Stephens, P. Briand, H. T. Mouridsen, K. Danø, and N. Brünner; The Complex between Urokinase and Its Type-1 Inhibitor in Primary Breast Cancer: Relation to Survival Cancer Res., December 1, 2000; 60(24): 6927 - 6934. [Abstract] [Full Text]

				M. N. Holten-Andersen, R. W. Stephens, H. J. Nielsen, G. Murphy, I. J. Christensen, W. Stetler-Stevenson, and N. Brunner High Preoperative Plasma Tissue Inhibitor of Metalloproteinase-1 Levels Are Associated with Short Survival of Patients with Colorectal Cancer Clin. Cancer Res., November 1, 2000; 6(11): 4292 - 4299. [Abstract] [Full Text] [PDF]

				K. Koli and J. Keski-Oja 1{{alpha}},25-Dihydroxyvitamin D3 and Its Analogues Down-Regulate Cell Invasion-associated Proteases in Cultured Malignant Cells Cell Growth Differ., April 1, 2000; 11(4): 221 - 229. [Abstract] [Full Text]

				E. Caputo, G. Manco, L. Mandrich, and J. Guardiola A Novel Aspartyl Proteinase from Apocrine Epithelia and Breast Tumors J. Biol. Chem., March 10, 2000; 275(11): 7935 - 7941. [Abstract] [Full Text] [PDF]

				K. Blackwell, Z. Haroon, G. Broadwater, D. Berry, L. Harris, J. D. Iglehart, M. Dewhirst, and C. Greenberg Plasma D-Dimer Levels in Operable Breast Cancer Patients Correlate With Clinical Stage and Axillary Lymph Node Status J. Clin. Oncol., February 1, 2000; 18(3): 600 - 600. [Abstract] [Full Text] [PDF]

				T. Kietzmann, U. Roth, and K. Jungermann Induction of the Plasminogen Activator Inhibitor-1 Gene Expression by Mild Hypoxia Via a Hypoxia Response Element Binding the Hypoxia-Inducible Factor-1 in Rat Hepatocytes Blood, December 15, 1999; 94(12): 4177 - 4185. [Abstract] [Full Text] [PDF]

				C. Bouchet, K. Hacene, P.-M. Martin, V. Becette, M. Tubiana-Hulin, S. Lasry, J. Oglobine, and F. Spyratos Dissemination Risk Index Based on Plasminogen Activator System Components in Primary Breast Cancer J. Clin. Oncol., October 1, 1999; 17(10): 3048 - 3057. [Abstract] [Full Text] [PDF]

				S. Schulze, K. M. Lyng, K. Bugge, A. Perner, A. Bendtsen, J. Thorup, H. J. Nielsen, V. Rasmussen, and J. Rosenberg Cardiovascular and Respiratory Changes and Convalescence in Laparoscopic Colonic Surgery: Comparison Between Carbon Dioxide Pneumoperitoneum and Gasless Laparoscopy Arch Surg, October 1, 1999; 134(10): 1112 - 1118. [Abstract] [Full Text] [PDF]

				D. Tong, C. Schneeberger, K. Czerwenka, R. K. Schmutzler, P. Speiser, E. Kucera, N. Concin, E. Kubista, S. Leodolter, and R. Zeillinger Messenger RNA Determination of Estrogen Receptor, Progesterone Receptor, pS2, and Plasminogen Activator Inhibitor-1 by Competitive Reverse Transcription-Polymerase Chain Reaction in Human Breast Cancer Clin. Cancer Res., June 1, 1999; 5(6): 1497 - 1502. [Abstract] [Full Text] [PDF]

				S Suzuki, Y Hayashi, Y Wang, T Nakamura, Y Morita, K Kawasaki, K Ohta, N Aoyama, S R Kim, H Itoh, et al. Urokinase type plasminogen activator receptor expression in colorectal neoplasms Gut, December 1, 1998; 43(6): 798 - 805. [Abstract] [Full Text] [PDF]

				H. J. Nielsen, H. Pappot, I. J. Christensen, N. Brünner, O. Thorlacius-Ussing, F. Moesgaard, K. Danø, and J. Grøndahl-Hansen Association between plasma concentrations of plasminogen activator inhibitor-1 and survival in patients with colorectal cancer BMJ, March 14, 1998; 316(7134): 829 - 830. [Full Text]

				T. H. Bugge, K. W. Kombrinck, Q. Xiao, K. Holmback, C. C. Daugherty, D. P. Witte, and J. L. Degen Growth and Dissemination of Lewis Lung Carcinoma in Plasminogen-Deficient Mice Blood, December 1, 1997; 90(11): 4522 - 4531. [Abstract] [Full Text] [PDF]

				C. D. Lox, C. A. Ronaghan, E. Cobos, and R. H. Messer Tamoxifen-Induced Changes in the Plasma Fibrinolytic Factors in Menopausal Women with Breast Cancer Clinical and Applied Thrombosis/Hemostasis, October 1, 1997; 3(4): 234 - 238. [Abstract] [PDF]

				R. W. Stephens, A. N. Pedersen, H. J. Nielsen, M. J. A. G. Hamers, G. Hoyer-Hansen, E. Ronne, E. Dybkjær, K. Dano, and N. Brunner ELISA determination of soluble urokinase receptor in blood from healthy donors and cancer patients Clin. Chem., October 1, 1997; 43(10): 1868 - 1876. [Abstract] [Full Text] [PDF]

				E. P. Diamandis, S. Nadkarni, B. Bhaumik, A. Abdelrahman, D. N. Melegos, G. Borchert, M. H. Black, M. Alonso, A. Salas, J. R. de los Toyos, et al. Immunofluorometric assay of pepsinogen C and preliminary clinical applications Clin. Chem., August 1, 1997; 43(8): 1365 - 1371. [Abstract] [Full Text] [PDF]

				M. Balbin and C. Lopez-Otin Hormonal Regulation of the Human Pepsinogen C Gene in Breast Cancer Cells. IDENTIFICATION OF A CIS-ACTING ELEMENT MEDIATING ITS INDUCTION BY ANDROGENS, GLUCOCORTICOIDS, AND PROGESTERONE J. Biol. Chem., June 21, 1996; 271(25): 15175 - 15181. [Abstract] [Full Text] [PDF]

				C.-I W. Q. Y. and Charles S. Craik and C. I. Wang Isolation of a High Affinity Inhibitor of Urokinase-type Plasminogen Activator by Phage Display of Ecotin J. Biol. Chem., May 19, 1995; 270(20): 12250 - 12256. [Abstract] [Full Text] [PDF]

				M. Parra, M. Jardi, M. Koziczak, Y. Nagamine, and P. Munoz-Canoves p53 Phosphorylation at Serine 15 Is Required for Transcriptional Induction of the Plasminogen Activator Inhibitor-1 (PAI-1) Gene by the Alkylating Agent N-Methyl-N'-nitro-N-nitrosoguanidine J. Biol. Chem., September 21, 2001; 276(39): 36303 - 36310. [Abstract] [Full Text] [PDF]