Plasminogen activator inhibitor type 2 in breast cancer.

C Duggan,Mj Duffy,N O'Higgins,C Barnes,E Mcdermott,Md Kramer,S Kennedy,P Elvin

doi:10.1038/bjc.1997.435

C Duggan, Mj Duffy + Show 6 more

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https://doi.org/10.1038/bjc.1997.435

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Abstract

The serine protease urokinase plasminogen activator (uPA) is causally involved in cancer invasion and metastasis. Activity of this protease in vivo is controlled principally by two inhibitors, one of which is plasminogen activator inhibitor type 2 (PAI-2). In this study, we show that PAI-2 levels were significantly higher in primary breast carcinomas (n = 152) than benign breast tumours (n = 18). In the primary cancers, PAI-2 levels correlated weakly but significantly with those of uPA and PAI-1, but not with tissue type plasminogen activator (tPA) or uPA receptor (uPAR) levels. Using Northern blotting, mRNA for PAI-2 was found in 28.6% of 49 primary breast cancers. In contrast to findings at the protein level, PAI-2 mRNA levels failed to correlate with those for uPA or PAI-1. After immunocytochemistry with primary cancers, PAI-2 was detected predominantly in the malignant cells of primary carcinomas but was also present in stromal cells. Using the median value as a cut-off point, PAI-2 showed no significant relationship with either disease-free interval or overall survival. However, using an optimum cut-off value, patients with low levels of PAI-2 had a worse outcome than those with a high level. We conclude that, unlike PAI-1, high levels of PAI-2 may be a favourable prognostic marker in breast cancer.

Highlights

Centrifugation was carried out at 10000 g for 20 min at 4°C. urokinase plasminogen activator (uPA), uPA receptor (uPAR), PAI- 1, plasminogen activator inhibitor type 2 (PAI-2) and type plasminogen activator (tPA) were assayed on the supernatant using enzyme-linked immunosorbent assay (ELISA)
Levels of PAI-2 were significantly higher in the primary carcinomas than in the benign tumours (P = 0.0006, Mann-Whitney U-test)
PAI-2 levels showed no significant relationship with either tumour size, nodal status or ER status

Summary

Methods

Assay of uPA, uPA receptor, tPA, PAI-1 and PAI-2 by enzyme-linked immunosorbent assay uPA, uPA receptor (uPAR), tPA, PAI-I and PAI-2 were all assayed as described previously (Duggan et al, 1995). The homogenate was centrifuged at 2000 g for 10 min and the supematant extracted with 1% Triton X-100. The PAI-1 assay detects both latent and active forms of PAI-I as well as PAI-I complexed to uPA. The PAI-2 ELISA detects both low and high molecular weight forms of this inhibitor as well as uPA-PAI-2 complexes. Of the 152 patients with primary breast cancer, follow-up information was available on 148. Levels of total protein were determined using the Bio-Rad Protein Assay (Bio-Rad)

Results

Discussion

Conclusion