Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer

The prognostic value of tissue-type plasminogen activator (tPA) measured in samples derived from 865 patients with primary breast cancer using a recen tly developed enzyme-linked immunosorbent assay (ELISA) was evaluated. Sinc e the assay could easily be adapted to the assessment of the complex of tPA with its type-1 inhibitor (PAI-1), it was investigated whether the tPA:PAI -1 complex also provides prognostic information. To this end, cytosolic ext racts and corresponding detergent extracts of 100 000 g pellets obtained af ter ultracentrifugation when preparing the cytosolic fractions for routine steroid hormone receptor determination were assayed. Statistically signific ant correlations were found between the cytosolic levels and those determin ed in the pellet extracts (Spearman correlation coefficient r(s) = 0.75, P < 0.001 for tPA and r = 0.50, P < 0.001 for tPA:PAI-1 complex), In both Cox univariate and multivariate analysis elevated levels of (total) tPA determ ined in the pellet extracts, but not in cytosols, were associated with prol onged relapse-free (RFS) and overall survival (OS). In contrast, high level s of the tPA:PAI-1 complex measured in cytosols, but not in the pellet extr acts, were associated with a poor RFS and OS. The prognostic information pr ovided by the cytosolic tPA:PAI-1 complex was comparable to that provided b y cytosolic (total) PAI-1. Furthermore, the estimated levels of free, uncom plexed tPA and PAI-1, in cytosols and in pellet extracts, were related to p atient prognosis in a similar way as the (total) levels of tPA and PAI-1 re spectively Determination of specific forms of components of the plasminogen activation system, i.e. tPA:PAI-1 complex and free, uncomplexed tPA and/or PAI-1, may be considered a useful adjunct to the analyses of the separate components (tPA and/or PAI-1) and provide valuable additional prognostic in formation with respect to survival of breast cancer patients.