Annals of Surgical Oncology

, Volume 10, Issue 8, pp 948–953 | Cite as

Nipple Aspirate Fluid Expression of Urokinase-Type Plasminogen Activator, Plasminogen Activator Inhibitor-1, and Urokinase-Type Plasminogen Activator Receptor Predicts Breast Cancer Diagnosis and Advanced Disease

  • Wenyi Qin
  • Weizhu Zhu
  • Colette Wagner-Mann
  • Edward R. SauterEmail author
Original Articles


Background: Tumor expression of urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and uPA receptor (uPAR) are breast cancer prognostic factors. Less is known about their usefulness in breast cancer diagnosis. Nipple aspirate fluid (NAF) is secreted into the breast duct and collected noninvasively, making it potentially useful both in breast cancer diagnosis and prognosis. We determined the association of uPA, PAI-1, and uPAR levels in NAF with breast cancer (1) detection and (2) advanced disease.

Methods: A total of 88 NAF specimens were collected from women with or without breast cancer, and uPA, PAI-1, and uPAR expression were measured by enzyme-linked immunosorbent assay.

Results: uPA and uPAR were independent predictors of cancer presence; uPAR was also an independent predictor of advanced disease stage. Higher PAI-1 expression in breast cancer that was found with univariate analysis was not observed after logistic regression was applied.

Conclusions: NAF evaluation of uPA, uPAR, and, perhaps, PAI-1 (significant only in univariate analysis) may provide useful breast cancer diagnostic and prognostic information.

Key Words

Urinary plasminogen activator Plasminogen activator inhibitor Nipple aspirate fluid Breast cancer 


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  1. 1.
    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.CrossRefPubMedGoogle Scholar
  2. 2.
    Tecimer C, Doering DL, Goldsmith LJ, Meyer JS, Abdulhay G, Wittliff JL. Clinical relevance of urokinase-type plasminogen activator, its receptor, and its inhibitor type 1 in endometrial cancer. Gynecol Oncol 2001;80:48–55.CrossRefPubMedGoogle Scholar
  3. 3.
    Chambers SK, Gertz RE Jr, Ivins CM, Kacinski BM. The significance of urokinase-type plasminogen activator, its inhibitors, and its receptor in ascites of patients with epithelial ovarian cancer. Cancer 1995;75:1627–33.CrossRefPubMedGoogle Scholar
  4. 4.
    Buo L, Meling GI, Karlsrud TS, Johansen HT, Aasen AO. Antigen levels of urokinase plasminogen activator and its receptor at the tumor-host interface of colorectal adenocarcinomas are related to tumor aggressiveness. Hum Pathol 1995;26:1133–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Pedersen H, Brunner N, Francis D, et al. Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res 1994;54:4671–5.PubMedGoogle Scholar
  6. 6.
    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. Nat Med 1995;1:1035–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Hofmann R, Lehmer A, Buresch M, Hartung R, Ulm K. Clinical relevance of urokinase plasminogen activator, its receptor, and its inhibitor in patients with renal cell carcinoma. Cancer 1996;78:487–92.CrossRefPubMedGoogle Scholar
  8. 8.
    Duffy MJ, O’Grady P, Devaney D, O’Siorain L, Fennelly JJ, Lijnen HJ. Urokinase-plasminogen activator, a marker for aggressive breast carcinomas. Preliminary report. Cancer 1988;62:531–3.CrossRefPubMedGoogle Scholar
  9. 9.
    Duggan C, Maguire T, McDermott E, O’Higgins N, Fennelly JJ, Duffy MJ. Urokinase plasminogen activator and urokinase plasminogen activator receptor in breast cancer. Int J Cancer 1995;61:597–600.CrossRefPubMedGoogle Scholar
  10. 10.
    Janicke 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;17:303–12.CrossRefPubMedGoogle Scholar
  11. 11.
    Foekens JA, Peters HA, Look MP, et al. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res 2000;60:636–43.PubMedGoogle Scholar
  12. 12.
    Look MP, van Putten WL, Duffy MJ, 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 2002;94:116–28.CrossRefPubMedGoogle Scholar
  13. 13.
    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 (uPA) and plasminogen activator inhibitor type 1 (n = 3424). Cancer Res 2002;62:4617–22.PubMedGoogle Scholar
  14. 14.
    Duffy MJ. Urokinase plasminogen activator and its inhibitor, PAI-1, as prognostic markers in breast cancer: from pilot to level 1 evidence studies. Clin Chem 2002;48:1194–7.PubMedGoogle Scholar
  15. 15.
    Sauter ER, Ross E, Daly M, et al. Nipple aspirate fluid: a promising non-invasive method to identify cellular markers of breast cancer risk. Br J Cancer 1997;76:494–501.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sauter ER, Chervoneva I, Diamandis A, Khosravi JM, Litwin S, Diamandis EP. Prostate-specific antigen and insulin-like growth factor binding protein-3 in nipple aspirate fluid are associated with breast cancer. Cancer Detect Prev 2002;26:149–57.CrossRefPubMedGoogle Scholar
  17. 17.
    Hsiung R, Zhu W, Klein G, et al. High basic fibroblast growth factor levels in nipple aspirate fluid are correlated with breast cancer. Cancer J 2002;8:303–10.CrossRefPubMedGoogle Scholar
  18. 18.
    Jankun J, Merrick HW, Goldblatt PJ. Expression and localization of elements of the plasminogen activation system in benign breast disease and breast cancers. J Cell Biochem 1993;53:135–44.CrossRefPubMedGoogle Scholar
  19. 18a.
    Janicke F, Prechtl A, Thomssen C, et al. Randomized adjuvant chemotherapy trial in high-risk, lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1. J Natl Cancer Inst 2001;93:913–20.CrossRefPubMedGoogle Scholar
  20. 19.
    Harbeck N, Kates RE, Schmitt M. 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 2002;20:1000–7.CrossRefPubMedGoogle Scholar
  21. 20.
    Chung HC, Rha SY, Park JO, et al. Physiological and pathological changes of plasma urokinase-type plasminogen activator, plasminogen activator inhibitor-1, and urokinase-type plasminogen activator receptor levels in healthy females and breast cancer patients. Breast Cancer Res Treat 1998;49:41–50.CrossRefPubMedGoogle Scholar
  22. 21.
    Blann AD, Gurney D, Wadley M, Bareford D, Stonelake P, Lip GY. Increased soluble P-selectin in patients with haematological and breast cancer: a comparison with fibrinogen, plasminogen activator inhibitor and von Willebrand factor. Blood Coagul Fibrinolysis 2001;12:43–50.CrossRefPubMedGoogle Scholar
  23. 22.
    Stephens RW, Pedersen AN, Nielsen HJ, et al. ELISA determination of soluble urokinase receptor in blood from healthy donors and cancer patients. Clin Chem 1997;43:1868–76.PubMedGoogle Scholar
  24. 23.
    Pedersen AN, Brunner N, Hoyer-Hansen G, et al. Determination of the complex between urokinase and its type-1 inhibitor in plasma from healthy donors and breast cancer patients. Clin Chem 1999;45:1206–13.PubMedGoogle Scholar
  25. 24.
    Rha SY, Yang WI, Gong SJ, et al. Correlation of tissue and blood plasminogen activation system in breast cancer. Cancer Lett 2000;150:137–45.CrossRefPubMedGoogle Scholar
  26. 25.
    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.CrossRefPubMedGoogle Scholar
  27. 26.
    de Witte JH, Foekens JA, Brunner N, et al. Prognostic impact of urokinase-type plasminogen activator receptor (uPAR) in cytosols and pellet extracts derived from primary breast tumours. Br J Cancer 2001;85:85–92.CrossRefPubMedGoogle Scholar
  28. 27.
    Guyton DP, Evans DM, Sloan-Stakleff KD. Urokinase plasminogen activator receptor (uPAR): a potential indicator of invasion for in situ breast cancer. Breast J 2000;6:130–6.CrossRefPubMedGoogle Scholar
  29. 28.
    Gong SJ, Rha SY, Chung HC, et al. Tissue urokinase-type plasminogen activator receptor levels in breast cancer. Int J Mol Med 2000;6:301–5.PubMedGoogle Scholar

Copyright information

© The Society of Surgical Oncology, Inc. 2003

Authors and Affiliations

  • Wenyi Qin
    • 1
  • Weizhu Zhu
    • 1
  • Colette Wagner-Mann
    • 1
  • Edward R. Sauter
    • 1
    • 2
    Email author
  1. 1.Department of SurgeryUniversity of MissouriColumbia
  2. 2.Department of SurgeryUniversity of Missouri-ColumbiaColumbia

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