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Submitted on February 21, 2003
Revised on April 2, 2003
Accepted on April 2, 2003

Tumour tissue concentrations of the proteinase inhibitors TIMP-1 and PAI-1 are complementary in determining prognosis in primary breast cancer

Anne-Sofie Schrohl, Anders N. Pedersen, Vibeke Jensen, Henning Mouridsen, Gillian Murphy, John A. Foekens, Nils Brünner, and Mads Nikolaj Holten-Andersen

Institute for Pharmacology and Pathobiology, The Royal Veterinary and Agricultural University, Frederiksberg C DK-1870

Corresponding Author: nbr{at}kvl.dk

The purpose of this study was to investigate the association between tumour tissue levels of total tissue inhibitor of metalloproteinases-1 (TIMP-1) and prognosis in patients with primary breast cancer and to analyse whether measurement of TIMP-1 in tumour extracts added prognostic information to that obtained from measurements of urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1). An established sandwich enzyme-linked immunosorbent assay (ELISA) was thoroughly validated for the measurement of total TIMP-1 in tumour tissue extracts and used to determine levels of total TIMP-1 in 341 detergent-extracted tumour tissue samples from patients with primary breast cancer. The median age of the patients was 56 years (range 29-75 years) and 164 were lymph node-negative and 177 were lymph node-positive. The median follow-up time of the patients was 8.5 years (range 7.3-11.3 years) and during follow-up 153 patients experienced recurrence of disease and 136 patients died. In univariate survival analysis, we found a significant association between tumour tissue TIMP-1 level and both shorter recurrence-free survival (p=0.0004) and shorter overall survival (p=0.03). In multivariate survival analysis, higher tumour tissue TIMP-1 levels significantly and independently predicted shorter recurrence-free survival (p<0.05, hazard ratios >1, comparing quartiles II-IV with I). In addition, we found that measurement of TIMP-1 levels added prognostic information to that obtained from measurement of PAI-1. In conclusion, high levels of TIMP-1 in tumour tissue extracts are significantly associated with a poor prognosis in patients with primary breast cancer. Furthermore, TIMP-1 adds prognostic information to that obtained from PAI-1. However, further validation in independent data sets is needed.


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