Download PDF
Thromb Haemost 2004; 91(03): 450-456
DOI: 10.1160/TH03-12-0798
Theme Issue Review Article
Schattauer GmbH

Urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1: novel tumor-derived factors with a high prognostic and predictive impact in breast cancer

Nadia Harbeck
1   Department of Obstetrics and Gynecology,Technical University of Munich, Germany
,
Ronald E. Kates
1   Department of Obstetrics and Gynecology,Technical University of Munich, Germany
,
Katja Gauger
1   Department of Obstetrics and Gynecology,Technical University of Munich, Germany
,
Amina Willems
1   Department of Obstetrics and Gynecology,Technical University of Munich, Germany
,
Marion Kiechle
1   Department of Obstetrics and Gynecology,Technical University of Munich, Germany
,
Viktor Magdolen
1   Department of Obstetrics and Gynecology,Technical University of Munich, Germany
,
Manfred Schmitt
1   Department of Obstetrics and Gynecology,Technical University of Munich, Germany
› Author Affiliations
Further Information

Publication History

Received 31 December 2003

Accepted after revision 20 January 2004

Publication Date:
05 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Urokinase-type plasminogen activator (uPA) and its inhibitor, PAI-1, play a key role in tumor invasion and metastasis. They were the first novel tumor biological factors to be validated at the highest level of evidence (LOE I) regarding their clinical utility in breast cancer. Their antigen levels are determined in tumor tissue extracts by standardized, quality-assured immunometric assays (ELISA). Since the late 1980s, numerous independent studies have demonstrated that patients with low levels of uPA and PAI-1 in their primary tumor tissue have a significantly better survival than patients with high levels of either factor. These prognostic data have recently been validated by an EORTC (European Organization for Research and Treatment of Cancer) pooled analysis comprising more than 8,000 breast cancer patients. In addition, results from a multicenter prospective randomized therapy trial in node-negative breast cancer (“Chemo N0”) showed that node-negative breast cancer patients with low levels of uPA and PAI-1 in their primary tumor have a very good prognosis, and may thus be candidates for being spared the burden of adjuvant chemotherapy. In contrast, node-negative patients with high uPA/PAI-1 are at substantially increased risk of disease recurrence, comparable to that of patients with three or more tumor cell positive axillary lymph nodes. The “Chemo N0” trial as well as retrospective data also indicate that these high-risk patients benefit from adjuvant chemotherapy. In conclusion, over a period of about 15 years sufficient evidence has been put forward to demonstrate that determination of uPA and PAI-1 in primary breast cancer patients supports risk-adapted individualized therapy decisions, particularily in patients with node-negative disease.

Keywords

Adjuvant therapy - metastasis - node-negative breast cancer - PAI-1 - prognosis - prediction of therapy response - risk group assessment - uPA
 

  • References

  • 1 Conese M, Blasi F. Urokinase/urokinase receptor system: internalization/degradation of urokinase-serpin complexes: mechanism and regulation. Biol Chem Hoppe Seyler 1995; 376: 143-55.
    PubMedGoogle Scholar
  • 2 Preissner KT, Kanse SM, May AE. Urokinase receptor: a molecular organizer in cellular communication. Curr Opin Cell Biol 2000; 12: 621-28.
    CrossrefPubMedGoogle Scholar
  • 3 Rosenberg S. New developments in the urokinase-type plasminogen activator system. Expert Opin Ther Targets 2001; 05: 711-22.
    CrossrefPubMedGoogle Scholar
  • 4 Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002; 03: 932-43.
    PubMedGoogle Scholar
  • 5 Reuning U, Magdolen V, Hapke S. et al. Molecular and functional interdependence of the urokinase-type plasminogen activator system with integrins. Biol Chem 2003; 384: 1119-31.
    PubMedGoogle Scholar
  • 6 Stefansson S, McMahon GA, Petitclerc E. et al. Plasminogen activator inhibitor-1 in tumor growth, angiogenesis and vascular remodeling. Curr Pharm Des 2003; 09: 1545-64.
    CrossrefPubMedGoogle Scholar
  • 7 Andreasen PA, Kjöller L, Christensen L. et al. The urokinase-type plasminogen activator system in cancer metastasis: A review. Int J Cancer 1997; 72: 1-22.
    CrossrefPubMedGoogle Scholar
  • 8 Schmitt M, Wilhelm OG, Reuning U. et al. The plasminogen activaton system as a novel target for therapeutic strategies. Fibrinolysis 2000; 14: 114-32.
    PubMedGoogle Scholar
  • 9 Sweep CGJ, Geurts-Moespot J, Grebenschikov N. et al. External quality assessment of transeuropean multicentre antigen determinations (ELISA) of urokinase-type plasminogen activator (uPA) and its type-1 inhibitor (PAI-1) in human breast cancer tissue extracts. Br J Cancer 1998; 78: 1434-41.
    CrossrefPubMedGoogle Scholar
  • 10 Sweep FC, Fritsche HA, Gion M. et al. EORTC-NCI Working Group. Considerations on development, validation, application, and quality control of immuno(metric) biomarker assays in clinical cancer research: an EORTCNCI working group report. Int J Oncol 2003; 23: 1715-26.
    PubMedGoogle Scholar
  • 11 Jänicke F, Pache L, Schmitt M. et al. Both the cytosols and detergent extracts of breast cancer tissues are suited to evaluate the prognostic impact of the urokinase-type plasminogen activator and its inhibitor, plasminogen activator inhibitor type 1. Cancer Res 1994; 54: 2527-30.
    PubMedGoogle Scholar
  • 12 Duffy MJ, O’Grady P, Devaney D. et al. Urokinase-plasminogen activator, a marker for aggressive breast cancers. Cancer 1998; 62: 531-3.
    PubMedGoogle Scholar
  • 13 Jänicke F, Schmitt M, Ulm K. et al. Urokinase-type plasminogen activator antigen and early relapse in breast cancer [letter]. Lancet 1989; 02 (8670) 1049.
    PubMedGoogle Scholar
  • 14 Jänicke F, Schmitt M, Hafter R. et al. Urokinase-type plasminogen activator (uPA) antigen is a predictor of early relapse in breast cancer. Fibrinolysis 1990; 04: 69-78.
    PubMedGoogle Scholar
  • 15 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. Sem Thromb Hemost 1991; 17: 303-12.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Jänicke F, Schmitt M, Pache L. et al. Urokinase (uPA) and its inhibitor PAI-1 are strong, independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat 1993; 24: 195-208.
    CrossrefPubMedGoogle Scholar
  • 17 Schmitt M, Harbeck N, Thomssen C. et al. Clinical impact of the plasminogen activation system in tumor invasion and metastasis: prognostic relevance and target for therapy. Thromb Haemost 1997; 78: 285-96.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Knoop A, Andreasen PA, Andersen JA. et al. Prognostic significance of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in primary breast cancer. Br J Cancer 1998; 77: 932-40.
    CrossrefPubMedGoogle Scholar
  • 19 Harbeck N, Thomssen C, Berger U. et al. Invasion marker PAI-1 remains a strong prognostic factor after long-term follow-up both for primary breast cancer and following first relapse. Breast Cancer Res Treat 1999; 54: 147-57.
    CrossrefPubMedGoogle Scholar
  • 20 Harbeck N, Dettmar P, Thomssen C. et al. Risk-group discrimination in node-negative breast cancer using invasion and proliferation markers: six-year median follow-up. Br J Cancer 1999; 80: 419-26.
    CrossrefPubMedGoogle Scholar
  • 21 Konecny G, Untch M, Arboleda J. et al. HER-2/neu and urokinase-type plasminogen activator and its inhibitor in breast cancer. Clin Cancer Res 2001; 07: 2448-57.
    PubMedGoogle Scholar
  • 22 Harbeck N, Kates RE, Look MP. et al. Enhanced benefit from adjuvant chemotherapy in breast cancer patients classified highrisk according to urokinase-type plasminogen activator (uPA) and and plasminogen activator inhibitor type 1 (n=3424). Cancer Res 2002; 62: 4617-22.
    PubMedGoogle Scholar
  • 23 Harbeck N, Kates R, Schmitt M. Clinical relevance of invasion factors uPA and PAI-1 for individualized therapy decisions in primary breast cancer is greatest when used in combination. J Clin Oncology 2002; 20: 1000-9.
    CrossrefPubMedGoogle Scholar
  • 24 Harbeck N, Alt U, Krüger A. et al. Prognostic impact of proteolytic factors (uPA, PAI-1, cathepsins B, D, L) in primary breast cancer reflects effects of adjuvant systemic therapy. Clin Cancer Res 2001; 07: 2757-64.
    PubMedGoogle Scholar
  • 25 Zemzoum I, Kates RE, Ross JS. et al. Invasion factors uPA/PAI-1 and HER2 status provide independent and complementary information on patient outcome in node-negative breast cancer. J Clin Oncol 2003; 21: 1022-8.
    CrossrefPubMedGoogle Scholar
  • 26 Look MP, van Putten WLJ, Duffy MJ. et al. Pooled analysis of prognostic impact of uPA and PAI-1 in 8,377 breast cancer patients. J Natl Cancer Inst 2002; 94: 116-28.
    CrossrefPubMedGoogle Scholar
  • 27 Jänicke F, Prechtl A, Thomssen C. et al. for the German Chemo N0 Study Group. Randomized adjuvant therapy trial in high-risk lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type I.. J Natl Cancer Inst 2001; 93: 913-20.
    CrossrefPubMedGoogle Scholar
  • 28 Harbeck N, Meisner C, Prechtl A. et al. for the German Chemo-N0 Study Group. Level-I evidence for prognostic and predictive impact of uPA and PAI-1 in node-negative breast cancer provided by second scheduled analysis of multicenter Chemo-N0 therapy trial. Breast Cancer Res Treat 2001; 69: 213.
    PubMedGoogle Scholar
  • 29 Muehlenweg B, Sperl S, Magdolen V. et al. Interference with the urokinase plasminogen activator system: a promising therapy concept for solid tumors. Exp Opin Biol Ther 2001; 01: 683-91.
    CrossrefPubMedGoogle Scholar
  • 30 Foekens JA, Look MP, Peters HA. et al. Urokinase-type plasminogen activator and its inhibitor PAI-1: predictors of poor response to tamoxifen therapy in recurrent breast cancer. J Natl Cancer Inst 1995; 17 87(10): 751-6.
    PubMedGoogle Scholar
  • 31 Hayes DF, Bast RC, Desch CE. et al. Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst 1996; 88: 1456-66.
    CrossrefPubMedGoogle Scholar
  • 32 McGuire W. Breast cancer prognostic factors: Evaluation guidelines. J Natl Cancer Inst 1991; 83: 154-5.
    CrossrefPubMedGoogle Scholar
  • 33 Hayes D. Do we need better prognostic factors in node-negative breast cancer? Arbiter. Eur J Cancer 2000; 36: 302-6.
    CrossrefPubMedGoogle Scholar
  • 34 Goldhirsch A, Wood WC, Gelber RD. et al. Meeting Highlights: updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol 2003; 21: 3357-65.
    CrossrefPubMedGoogle Scholar
  • 35 Piccart MJ, Sotiriou C, Cardoso F. New data on chemotherapy in the adjuvant setting. Breast 2003; 12: 373-8.
    CrossrefPubMedGoogle Scholar
  • 36 Heiss MM, Allgayer H, Gruetzner KU. et al. Individual development and uPA-receptor expression of disseminated tumour cells in bone marrow: a reference to early systemic disease in solid cancer. Nature Med 1995; 01: 1035-9.
    CrossrefPubMedGoogle Scholar
  • 37 Sperl S, Mueller MM, Wilhelm OG. et al. The uPA/uPA receptor system as a target for tumor therapy. Drug News Perspect 2001; 14: 401-11.
    CrossrefPubMedGoogle Scholar
  • 38 Wilex AG. Munich,Germany: Press release 10-14-02. www.wilex.de.
  • 39 Krol J, Kopitz C, Kirschenhofer A. et al. Inhibition of intraperitoneal tumor growth of human ovarian cancer cells by bi-and trifunctional inhibitors of tumor-associated proteolytic systems. Biol Chem 2003; 384: 1097-102.
    PubMedGoogle Scholar
  • 40 Reuning U, Sperl S, Kopitz C. et al. Urokinase-type plasminogen activator (uPA) and its receptor (uPAR): development of antagonists of uPA/uPAR interaction and their effects in vitro and in vivo. Curr Pharm Des 2003; 09: 1529-43.
    CrossrefPubMedGoogle Scholar
  • 41 Foekens JA, Schmitt M, van Putten WL. et al. Plasminogen activator inhibitor-1 and prognosis in primary breast cancer. J Clin Oncology 1994; 12: 1648-58.
    CrossrefPubMedGoogle Scholar
  • 42 Grondahl-Hansen J, Peters HA, van Putten WL. et al. Prognostic significance of the receptor for urokinase plasminogen activator in breast cancer. Clin Cancer Res 1995; 01: 1079-87.
    PubMedGoogle Scholar
  • 43 Fernö M, Bendahl PO, Borg A. et al. Urokinase plasminogen activator, a strong independent prognostic factor in breast cancer, analysed in steroid receptor cytosols with a luminometric immunoassay. Eur J Cancer 1996; 32A: 793-801.
    PubMedGoogle Scholar
  • 44 Eppenberger U, Kueng W, Schlaeppi JM. et al. Markers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients. J Clin Oncol 1998; 16: 3129-36.
    CrossrefPubMedGoogle Scholar
  • 45 Kim SJ, Shiba E, Kobayashi T. et al. Prognostic impact of urokinase-type plasminogen activator (PA), PA inhibitor type-1 and tissue-type PA antigen levels in node-negative breast cancer: a prospective study on multicenter basis. Clin Cancer Res 1998; 04: 177-82.
    PubMedGoogle Scholar
  • 46 Kute TE, Grondahl-Hansen J, Shao SM. et al. Low cathepsin D and low plasminogen activator type 1 inhibitor in tumor cytosols defines a group of node negative breast cancer patients with low risk of recurrence. Breast Cancer Res Treat 1998; 47: 9-16.
    CrossrefPubMedGoogle Scholar
  • 47 Bouchet C, Hacene K, Martin PM. et al. Dissemination index based on plasminogen activator system components in primary breast cancer. J Clin Oncol 1999; 17: 3048-57.
    CrossrefPubMedGoogle Scholar
  • 48 Foekens JA, Peters HA, Look MP. et al. Urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res 2000; 60: 636-43.
    PubMedGoogle Scholar
  • 49 Hansen S, Overgaard J, Rose C. et al. Independent prognostic value of angiogenesis and the level of plasminogen activator inhibitor type 1 in breast cancer patients. Br J Cancer 2003; 88: 102-8.
    CrossrefPubMedGoogle Scholar