Urokinase-Type Plasminogen Activator and PAI-1

Validated Prognostic Factors for Breast Cancer
  • Michael J. Duffy
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Urokinase plasminogen activator (uPA) is a serine protease causally involved in tumor progression. In vivo, uPA can be inhibited by the serpin inhibitor plasminogen activator inhibitor-1 (PAI-1). However, PAI-1 is a multifunctional protein that can also play a role in cell migration, cell adhesion, angiogenesis, and apoptosis. Multiple single-institutional studies have shown that both uPA and PAI-1 are potent and independent prognostic factors in breast cancer. Recently, this prognostic impact was validated in both a prospective randomized trial and a pooled analysis. As well as being prognostic, high levels of uPA/PAI-1 have been shown to predict for relative resistance to hormone therapy in patients with advanced breast cancer but are associated with an enhanced response to adjuvant chemotherapy in early breast cancer. As uPA and PAI-1 are both prognostic and predictive, assay of these factors has the potential to result in the enhanced management of patients with breast cancer. Measurement of these analytes should thus be now considered for use in the routine management of patients with breast cancer.

Key Words

Urokinase plasminogen activator PAI-1 cancer tumor marker Level 1 evidence 


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  1. 1.
    Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002;2:563–572.PubMedCrossRefGoogle Scholar
  2. 2.
    Helenius, MA Saramaki, OR, Linja MJ, Tammela, TLJ, Visakorpi T. Amplification of urokinase gene in prostate cancer. Cancer Res 2001;61:5340–5344.PubMedGoogle Scholar
  3. 3.
    Andreasen PA, Kjoller L, Christensen L, Duffy MJ. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 1997;72:1–22.PubMedCrossRefGoogle Scholar
  4. 4.
    Carmeliet P, Moons L, Lijnen R, et al. Urokinase-generated plasmin activates matrix metalloproteinase during aneurysm formation. Nat Genet 1997;17:439–444.PubMedCrossRefGoogle Scholar
  5. 5.
    Rifkin DB. Cross-talk among proteases and matrix in the control of growth factor action. Fibrinol Proteol 1997;11:3–9.CrossRefGoogle Scholar
  6. 6.
    Magdolen V, Rettenberger P, Koppitz M, Goretzki L, Kessler H, Weidle U. Systematic mutational analysis of the receptor-binding region of the human urokinase-type plasminogen activator. Eur J Biochem 1996;237:743–751.PubMedCrossRefGoogle Scholar
  7. 7.
    Liang OD, Chavakis T, Kanse SM, Preissner KT. Ligand binding region in the receptor for urokinase-type plasminogen activator. JBiol Chem 2001;276,28946–28953.CrossRefGoogle Scholar
  8. 8.
    Ossowski L, Aguirre JA. Urokinase receptor and integrin partnership: coordination of signalling for cell adhesion, migration and growth. Curr Opin Cell Biol 2000;12:613–620.PubMedCrossRefGoogle Scholar
  9. 9.
    Andreasen PA, Egelund R, Petersen HH. The plasminogen activation system in tumor growth, invasion and metastasis. Cell Mol Life Sci 2000;57:25–40.PubMedCrossRefGoogle Scholar
  10. 10.
    Schroeck F, de Prada NA, Sperl S, et al. Interaction of plasminogen activator inhibitor type-1 (PAI-1) with vitronectin (Vn): mapping the binding sites on PAI-1 and Vn. Biol Chem 2002;383:1143–1149.PubMedCrossRefGoogle Scholar
  11. 11.
    Loskutoff, DJ, Curriden SA, Hu G, Deng G. Regulation of cell adhesion by PAI-1, Review article. APMIS 1999;107:54–61.PubMedCrossRefGoogle Scholar
  12. 12.
    Hoylaerts M, Rijken DC, Lijnen HR, Collen D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J Biol Chem 1982;257:2912–2919.PubMedGoogle Scholar
  13. 13.
    Ehrlich HJ, Keijer J, Preissner KT, et al. Functional interaction of PAI-1 and heparin. Biochemistry 1991;30:1021–1028.PubMedCrossRefGoogle Scholar
  14. 14.
    Kwaan HC, Wang J, Svoboda K, Declerck PJ. Plasminogen activator inhibitor 1 may promote tumor growth through inhibition of apoptosis. Br J Cancer 2000;82:1702–1708.PubMedCrossRefGoogle Scholar
  15. 15.
    Janicke F, Schmitt M, Hafter A. Urokinase-type plasminogen activator (uPA) antigen is a predictor of early relapse in breast cancer. Fibrinolysis 1990;4:6978.CrossRefGoogle Scholar
  16. 16.
    Reilly D, Christensen L, Duch M, et al. Type-1 plasminogen activator inhibitor in human breast carcinomas. Int J Cancer 1992;50:208–214.PubMedCrossRefGoogle Scholar
  17. 17.
    Duggan C, Maguire T, McDermott E, et al. Urokinase plasminogen activator and urokinase plasminogen activator receptor in breast cancer. Int J Cancer 1995;61:597–600.PubMedCrossRefGoogle Scholar
  18. 18.
    Mangel WF, Toledo DL, Nardulli AM, et al. Plasminogen activator in human breast cancer cell lines: hormonal regulation and properties. J Steroid Biochem 1988;30:79–88.PubMedCrossRefGoogle Scholar
  19. 19.
    Pourreau-Schneider N, Delori P, Boutiere B, et al. Modulation of plasminogen activator systems by matrix components in 2 breast cancer cell lines: MCF-7 and MDA-MB-231. J Natl Cancer Inst 1989;81:259–266.PubMedCrossRefGoogle Scholar
  20. 20.
    Korczak B, Kerbel RS, Dennis JW. Autocrine and paracrine regulation of tissue inhibitor of metalloproteinases, transin and urokinase gene expression in meta-static and nonmetastatic mammary carcinoma cells. Cell Growth Differ 1991;2:335–341.PubMedGoogle Scholar
  21. 21.
    Long BJ, Rose DP. Invasive capacity and regulation of urokinase-type plasminogen activator in estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells and a transfection (S30) stably expressing ER. Cancer Lett 1996:99:209–215.PubMedCrossRefGoogle Scholar
  22. 22.
    Levenson AS, Kwaan HC, Svoboda KM, et al. Oestradiol regulation of the components of the plasminogen-plasmin system in MDA-MB-231 human breast cancer cells stably expressing the oestrogen receptor. Br J Cancer 1998;78:88–95.PubMedGoogle Scholar
  23. 23.
    Sieuwerts AM, Klijn JG, Henzen-Logmans SC, et al. Cytokine-regulated uroki-nase-type-plasminogen activator (uPA) production by human breast fibroblasts in vitro. Breast Cancer Res Treat 1999;55:9–20.PubMedCrossRefGoogle Scholar
  24. 24.
    Dunn SE, Torres JV, Nihei N, Barrett JC. The insulin-like growth factor-1 elevates urokinase-type plasminogen activator in human breast cancer cells: a new avenue for breast cancer therapy. Mol Carcinogen 2000;27:10–17.CrossRefGoogle Scholar
  25. 25.
    Lin VC, Eng AS, Hen NE, et al. Effect of progesterone on the invasive properties and tumor growth of progesterone receptor-transfected breast cancer cells MDA-MB-231. Clin Cancer Res 2001;7:2880–2886.PubMedGoogle Scholar
  26. 26.
    Silvy M, Giusti C, Martin PM, Berthois Y. Differential regulation of cell proliferation by epidermal growth and amphiregulin in tumoral versus normal breast epithelial cells. Br J Cancer 2001;84:936–945.PubMedCrossRefGoogle Scholar
  27. 27.
    Puricelli L, Proiettii CJ, Labriola L, et al. Heregulin inhibits proliferation viaERKs and phosphatidylinositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells. Int J Cancer 2002;100:642–653.PubMedCrossRefGoogle Scholar
  28. 28.
    Guo Y, Pakneshan P, Gladu J, et al. Regulation of DNA methylation in human breast cancer: effect on the urokinase-type plasminogen activator tgene production and tumor invasion. J Biol Chem 2002;277:41571–41579.PubMedCrossRefGoogle Scholar
  29. 29.
    Watabe, T, Yoshida K, Shindoh M, et al. The ets-1 and ets-2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor. Int J Cancer 1998;77:128–137.PubMedCrossRefGoogle Scholar
  30. 30.
    LookM P, van Putten WLJ, Duffy MJ, et al. Pooled analysis of prognostic impact of tumor biological factors uPA and PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst 2002;94:116–128.PubMedGoogle Scholar
  31. 31.
    Del Vecchio S, Stoppelli MP, Carriero MV, et al. Human urokinase receptor concentration in malignant and benign breast tumors by in vitro quantitative autoradiography: comparison with urokinase levels. Cancer Res 1993;53:3198–3206.PubMedGoogle Scholar
  32. 32.
    Jankum J, Merrick HW, Goldblatt PJ. Expression and localisation of elements of the plasminogen activation system in benign breast disease and breast cancer. J Cell Biochem 1993;53:135–144.CrossRefGoogle Scholar
  33. 33.
    Christensen L, Simonsen ACW, Heegaard CW, et al. Immunohistochemical localisation of urokinase-type plasminogen activator, type-1 plasminogen activator inhibitor, urokinase receptor and alpha-2-macroglobulin receptor in human breast carcinomas. Int J Cancer 1996;66:441–452.PubMedCrossRefGoogle Scholar
  34. 34.
    Kennedy S, Duffy MJ, Duggan C, et al. Semi-quantitation of plasminogen activator and its receptor in breast carcinomas by immunocytochemistry. Br J Cancer 1998;77:1638–1641.PubMedGoogle Scholar
  35. 35.
    Nielsen BS, Sehested M, Duun S, et al. Urokinase plasminogen activator is localized in stromal cells in ductal breast cancer. Lab Invest 2001;81:1485–1501.PubMedGoogle Scholar
  36. 36.
    Nielsen BS, Sehested M, Timshel S, et al. Messenger mRNA for urokinase plasminogen activator (uPA) is expressed in myofibroblasts adjacent to cancer cells in human breast cancer. Lab Invest 1996;74:168–177.PubMedGoogle Scholar
  37. 37.
    Duffy MJ. Then role of proteolytic enzymes in cancer invasion and metastasis. Clin Exp Med 1992;10:145–155.CrossRefGoogle Scholar
  38. 38.
    Duffy MJ. Urokinase-type plasminogen activator: a potent marker of metastatic potential in human cancer. Biochem Soc Trans 2002;30:207–210.PubMedCrossRefGoogle Scholar
  39. 39.
    Duffy MJ: Do proteases play a role in cancer invasion and metastasis? Eur J Cancer Clin Oncol 1987;23:583–589.PubMedCrossRefGoogle Scholar
  40. 40.
    Duffy MJ, O’Grady P, Devaney D, O’Siorain L, Fennelly JJ, Lijnen RJ. Uroki-nase-plasminogen activator, a marker for aggressive breast cancer. Preliminary report. Cancer 1988;62:531–533.PubMedCrossRefGoogle Scholar
  41. 41.
    Duffy MJ, Reilly D, O’Sullivan C, O’Higgins N, Fennelly JJ. Urokinase plasminogen activator and prognosis in breast cancer. Lancet 1990;335:109.CrossRefGoogle Scholar
  42. 42.
    Janicke F, Schmitt M, Ulm K, Gossner W, Graeff H. Urokinase-type plasminogen activator antigen and early relapse in breast cancer. Lancet 1989;ii:1049.CrossRefGoogle Scholar
  43. 43.
    Spryatos F, Martin P-M, Hacene K, et al. Multiparametric prognostic evaluation of biological factors in primary breast cancer. J Natl Cancer Inst 1992;84:1266–1272.CrossRefGoogle Scholar
  44. 44.
    Cook D, Mahmoud-Alexandroni N, Gaffney PJ, et al. Plasminogen activators are powerful indicators of prognosis in breast cancer. Br J Surg 1991;78:1495.Google Scholar
  45. 45.
    Foekens J, Schmitt M, Pache L, et al. Prognostic value of urokinase-type plasminogen activator in 671 primary breast cancer patients. Cancer Res 1992;52:6101–6105.PubMedGoogle Scholar
  46. 46.
    Grondahl-Hansen J, Christensen IJ, Rosenquist C, et al. High levels of urokinase-type plasminogen activator and its inhibitor PAI-1 in cytosolic extracts of breast carcinoma are associated with poor prognosis. Cancer Res 1993;53:2513–2521.PubMedGoogle Scholar
  47. 47.
    Bouchet C, Spyratos F, Martin P-M, et al. Prognostic role of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in breast carcinomas. Br J Cancer 1994;69:398–405.PubMedGoogle Scholar
  48. 48.
    Sumiyoshi K, Urano T, Takada Y, Takada A. PAI-1 and PAI-2 levels as predictors in staging malignancy in breast cancer. In: Glas-Greenwalt P, ed. Fibrinolysis in Disease, CRC Press, Boca Raton, FL, 1995:26–30.Google Scholar
  49. 49.
    Ferno M, Bendahl PO, Borg A, et al. Urokinase plasminogen activator, a strong independent prognostic factor in breast cancer: analysed in steroid receptor cyto-sols with a luminometric immunoassay. Eur J Cancer 1996;32A:793–801.PubMedCrossRefGoogle Scholar
  50. 50.
    Shiba E, Kim SJ, Taguchi T, et al. A prospective study on the prognostic significance of urokinase-type plasminogen activator levels in breast cancer tissue. J Cancer Res Clin Oncol 1997;123:555–559.PubMedCrossRefGoogle Scholar
  51. 51.
    Umeda T, Eguchi Y, Okino K, et al. Cellular localisation of urokinase-type plasminogen activator, its inhibitors and their mRNA in breast cancer tissue. J Pathol 1997;183:388–397.PubMedCrossRefGoogle Scholar
  52. 52.
    Knoop A, Andreasen PA, Anderson JA, et al. Prognostic significance of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in primary breast cancer. Br J Cancer 1998;77:932–940.PubMedGoogle Scholar
  53. 53.
    Peyrat J-P, Vanlemmens L, Fournier J, et al. Prognostic value of p53 and urokinase-type plasminogen activator in node-negative human breast cancer. Clin Cancer Res 1998;4:189–196.PubMedGoogle Scholar
  54. 54.
    Kim SJ, Shiba E, Kobayashi T, et al. Prognostic impact of urokinase-type plasminogen activator (uPA), 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;4:177–182.PubMedGoogle Scholar
  55. 55.
    Tetu B, Brisson J, Lapointe H. Prognostic significance of stromelysin 3, gelatinase A and urokinase expression in breast cancer. Hum Pathol 1998;29:979–985.PubMedCrossRefGoogle Scholar
  56. 56.
    Eppenberger U, Kueng W, Schlaeppi J-M, 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;16:3129–3136.PubMedGoogle Scholar
  57. 57.
    Kute TE, Grondahl-Hansen J, Shao S-M, et al. Low cathepsin D and low plasminogen activator type 1 inhibitor in tumor cytosols define a group of node-negative breast cancer patients with low risk of recurrence. Breast Cancer Res Treat 1998;47:9–16.PubMedCrossRefGoogle Scholar
  58. 58.
    Broet P, Spyratos F, Romain S, et al. Prognostic value of uPA and p53 accumulation measured by quantitative biochemical assays in 1245 primary breast cancer patients: a multicenter study. Br J Cancer 1999;80:536–545.PubMedCrossRefGoogle Scholar
  59. 59.
    Konecny G, Untch M, Arboleda J, et al. HER-2 and urokinase-type plasminogen activator and its inhibitor in breast cancer. Clin Cancer Res 2001;7:2448–2457.PubMedGoogle Scholar
  60. 60.
    Malmstrom P, Bendahl P-O, Boiesen P, et al. S-phase fraction are urokinase plasminogen activator are better markers for distant recurrences that Nottingham Prognostic Index and histological grade in aprospective study of premenopausal lymph node-negative breast cancer. J Clin Oncol 2001;19:2010–2019.PubMedGoogle Scholar
  61. 61.
    Meo S, Dittadi R, Sweep CGJ, et al. Prognostic value of VEGF, uPA, PAI-1 in 196 node negative breast cancers. Int J Biol Markers 2002;17:S44.Google Scholar
  62. 62.
    Harbeck N, Dettmar C, Thomssen C, et al. Risk-group discrimination in node-negative breast cancer using invasion and proliferation markers: 6-year median follow-up. Br J Cancer 1999;80:419–426.PubMedCrossRefGoogle Scholar
  63. 63.
    Le Goff JM, Lavayssiere L, Rouesse J, Spyratos F. Nonlinear discriminant analysis and prognostic factor classification in node-negative primary breast cancer using probabilistic neural networks. Anticancer Res 2000;20:2213–2218.PubMedGoogle Scholar
  64. 64.
    Duffy MJ, Duggan C, Maguire T, et al. Urokinase plasminogen activator as a predictor of aggressive disease in breast cancer. Enzyme Protein 1996;49:85–93.PubMedGoogle Scholar
  65. 65.
    Harbeck N, Kates RE, Schmitt M. Clinical relevance of invasion factors urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 for individualized therapy in primary breast cancer is greatest when used in combination. J Clin Oncol 2002;20:1000–1007.PubMedCrossRefGoogle Scholar
  66. 66.
    Duffy MJ, Reilly D, McDermott E, et al. Urokinase plasminogen activator as a prognostic marker in different subgroups of patients with breast cancer. Cancer 1994;74:2276–2280.PubMedCrossRefGoogle Scholar
  67. 67.
    Janicke F, Schmitt M, Graeff H. Clinical relevance of the urokinase-type and tissue-type plasminogen activators and their type 1 inhibitor in breast cancer. Semin Thromb Hemostas 1991;17:303–312.CrossRefGoogle Scholar
  68. 68.
    Foekens JA, Schmitt M, van Putten WLJ, et al. Plasminogen activator inhibitor-1 and prognosis in primary breast cancer. J Clin Oncol 1994;12:1648–1658.PubMedGoogle Scholar
  69. 69.
    Duggan C, Kennedy S, Kramer MD, et al. Plasminogen activator inhibitor type 2 in breast cancer. Br J Cancer 1997;76:622–627.PubMedGoogle Scholar
  70. 70.
    Billgren AM, Ritqvist LE, Johansson H, Hagerstrom T, Skoog L. The role of cathepsin D and PAI-1 in primary invasive breast cancer as prognosticators and predictors of treatment with adjuvant tamoxifen. Eur J Cancer 2000;36:1374–1380.PubMedCrossRefGoogle Scholar
  71. 71.
    Janicke F, Schmitt M, Pache L, et al. Urokinase plasminogen activator (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat 1993;24:195–208.PubMedCrossRefGoogle Scholar
  72. 72.
    Bajou K, Noel A, Gerard RD, et al. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 1998;4:923–928.PubMedCrossRefGoogle Scholar
  73. 73.
    Bajou K, Masson V, Gerard RD, et al. The plasminogen activator inhibitor PAI-1 controls in vivo vascularization by interaction with proteases, not vitronectin: implications for antioangiogenic strategies. J Cell Biol 2001;152:777–784.PubMedCrossRefGoogle Scholar
  74. 74.
    Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell 2002;108:153–164.PubMedCrossRefGoogle Scholar
  75. 75.
    Benraad TH, Geurts-Moespot J, Grondahl-Hansen J, et al. Immunoassays (ELISA) of urokinase-type plasminogen activator (uPA): report of an EORTC/BIOMED-1 Workshop. Eur J Cancer 1996;32:1371–1381.CrossRefGoogle Scholar
  76. 76.
    Sweep CGJ, Geurts-Moespot J, Grebenschikov N, et al. External quality assessment of trans-European multicenter antigen determination (enzyme-linked immunosorbent assay) of urokinase plasminogen activator (uPA) and its type-1 inhibitor (PAI-1) in human breast cancer extracts. Br J Cancer 1998;78:1434–1441.PubMedGoogle Scholar
  77. 77.
    Hayes D, 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;88:1456–1466.PubMedCrossRefGoogle Scholar
  78. 78.
    Janicke F, Prechtl A, Thomssen C, et al. For the German Chemo No Study Group. Randomized adjuvant chemotherapy trial in high-risk node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1. J Natl Cancer Inst 2001;93:913–920.PubMedCrossRefGoogle Scholar
  79. 79.
    Clark GM. Do we really need prognostic factors for breast cancer? Breast Cancer Res Treat 1994;30:117–126.PubMedCrossRefGoogle Scholar
  80. 80.
    Foekens J, 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;87:751–756.PubMedCrossRefGoogle Scholar
  81. 81.
    Harbeck N, Kates RE, Look MP, et al. Enhanced benefit from adjuvant chemotherapy in breast cancer patients classified high-risk according to urokinase-type plasminogen activator (uP A) and plasminogen activator inhibitor type 1 (N = 3424). Cancer Res 2002;62:4617–4622.PubMedGoogle Scholar
  82. 82.
    Schmitt M, Magdolen V, Sperl S, et al. Interference with the urokinase plasminogen activator system: a promising therapy concept for solid tumors. Expert Opinion Biol Ther 2001;1:683–691.CrossRefGoogle Scholar
  83. 83.
    Schmitt M, Eickler A, Welk A, et al. Procedure for the quantitative protein determination of urokinase (uPA) and its inhibitor PAI-1 in human breast cancer tissue extracts by ELISA. In: Harris A, Brooks S, eds., Breast Cancer Protocols, Humana Press, Totowa, NJ.Google Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Michael J. Duffy
    • 1
  1. 1.Department of Nuclear MedicineSt. Vincent’s HospitalDublinIreland

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