Complex of urokinase-type plasminogen activator with its type 1 inhibitor predicts poor outcome in 576 patients with lymph node-negative breast carcinoma.

Abstract

The ability of a solid tumor to grow and metastasize has a significant dependence on protease systems, such as the plasminogen activation system. The plasminogen activation system includes the urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1), among other molecules. Both uPA and PAI-1 are established prognostic factors for patients with breast carcinoma. In the current study, the authors investigated whether the complex of uPA with PAI-1 is also associated with the natural course of this malignancy. Cytosolic levels of uPA, PAI-1, and the uPA:PAI-1 complex were measured in tumor tissue from 576 patients with lymph node-negative invasive breast carcinoma using quantitative enzyme-linked immunosorbent assays. Patients did not receive adjuvant systemic therapy, and the median follow-up duration was 61 months (range, 2-187 months) after primary diagnosis. Correlations with well known clinicopathologic factors were assessed, and univariate and multivariate survival analyses were performed. uPA:PAI-1 complex levels were positively associated with adverse histologic grade and inversely correlated with estrogen and progesterone receptor status. On univariate analysis, increased levels of the uPA:PAI-1 complex were found to be associated with reduced recurrence-free survival (RFS) and overall survival (OS) rates. On multivariate analysis, uPA:PAI-1 complex levels were found to be an independent predictor of OS (P = 0.039), but not RFS (P = 0.240). When uPA and PAI-1 levels were not included in the multivariate analysis, uPA:PAI-1 complex levels became a significant predictor of both RFS and OS (P = 0.029 and P = 0.007, respectively). The results of the current study demonstrate that uPA:PAI-1 complex levels have prognostic value on univariate analysis. In addition, increased uPA:PAI-1 complex levels were significantly associated with poor OS on multivariate analysis. Increased uPA:PAI-1 complex levels were also significantly associated with reduced RFS rates after the exclusion of uPA and PAI-1 levels from the multivariate analysis model.