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The Complex between Urokinase and Its Type-1 Inhibitor in Primary Breast Cancer: Relation to Survival

The Finsen Laboratory, Rigshospitalet [A. N. P., I. J. C., R. W. S., K. D., N. B.]; Department of Tumor Endocrinology, the Danish Cancer Society [P. B.]; and the Danish Breast Cancer Cooperative Group [H. T. M.], DK-2100 Copenhagen, Denmark

We examined the relationship between tumor tissue level of the complex formed of urokinase (uPA) and its type-1 inhibitor (PAI-1) and survival of breast cancer patients. The study included 342 axillary lymph node-negative and -positive primary breast cancer patients with a median follow-up of 67 months. Using a newly established ELISA, the levels of preformed uPA·PAI-1 complex were measured in tumor tissue extracts and analyzed with respect to total uPA, total PAI-1, and clinicopathological parameters, including survival. uPA·PAI-1 complex comprised a minor, variable fraction of both total uPA and PAI-1 levels. The complex levels were higher in node-negative tumors than in node-positive tumors and higher in small and low-grade tumors (all, P 0.002). The tumor levels of complex, uPA, and PAI-1 were all associated with survival; high complex levels predicted longer recurrence-free survival (P = 0.03) and overall survival [OS (P = 0.005)], whereas high uPA or PAI-1 levels significantly predicted shorter survival. In multivariate Cox analysis, the only parameters that independently predicted survival were total PAI-1 level and lymph node status for recurrence-free survival and OS and, additionally, steroid hormone receptor status and grade for OS. This is the first demonstration of a relationship between uPA·PAI-1 complex tumor level and patient survival. However, total PAI-1 level showed superior prognostic power. Additional studies are needed to understand the relationship of these parameters to cancer biology and to assess the clinical utility of the uPA·PAI-1 complex.

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