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Molecular & Cellular Proteomics 2:164-172, 2003.
© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Tumor Tissue Concentrations of the Proteinase Inhibitors Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) and Plasminogen Activator Inhibitor Type 1 (PAI-1) Are Complementary in Determining Prognosis in Primary Breast Cancer ^*

Anne-Sofie Schrohl^,, Ib Jarle Christensen, Anders N. Pedersen^¶, Vibeke Jensen^,, Henning Mouridsen^¶, Gillian Murphy^||, John A. Foekens^**, Nils Brünner^,, and Mads Nikolaj Holten-Andersen^,

The Finsen Laboratory, Rigshospitalet dept. 8621, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
Institute for Pharmacology and Pathobiology, The Royal Veterinary and Agricultural University, Ridebanevej 9, DK-1870 Frederiksberg C, Denmark
^¶ Department of Oncology, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
^|| Department of Oncology, Cambridge Institute for Medical Research, Cambridge University, Wellcome Trust/Medical Research Council Building, Room 6.9/11, Hills Road, Cambridge CB2 2XY, United Kingdom
^** Erasmus MC-Daniel der Hoed, Josephine Nefkens Building, Room BE 426, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

The purpose of this study was to investigate the association between tumor tissue levels of total tissue inhibitor of metalloproteinases-1 (TIMP-1) and prognosis in patients with primary breast cancer and to analyze whether measurement of TIMP-1 in tumor extracts added prognostic information to that obtained from measurements of urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 (PAI-1). An established sandwich enzyme-linked immunosorbent assay was thoroughly validated for the measurement of total TIMP-1 in tumor tissue extracts and used to determine levels of total TIMP-1 in 341 detergent-extracted tumor 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 tumor 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 tumor 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 tumor 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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