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Originally published In Press as doi:10.1074/mcp.M400209-MCP200 on January 8, 2005.
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Molecular & Cellular Proteomics 4:483-491, 2005.
© 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

Research

Measurement of the Uncomplexed Fraction of Tissue Inhibitor of Metalloproteinases-1 in the Prognostic Evaluation of Primary Breast Cancer Patients*

Sidse Ørnbjerg Würtz{ddagger},§, Ib Jarle Christensen, Anne-Sofie Schrohl{ddagger}, Henning Mouridsen||, Ulrik Lademann{ddagger}, Vibeke Jensen{ddagger} and Nils Brünner{ddagger}

From the {ddagger} Department of Veterinary Pathobiology, The Royal Veterinary and Agricultural University, Ridebanevej 9, DK-1870 Frederiksberg C, Department of Surgical Gastroenterology, Hvidovre Hospital, DK-2650 Hvidovre, and || Department of Oncology, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark

Several studies have demonstrated an association between high tumor tissue levels of total tissue inhibitor of metalloproteinases-1 (TIMP-1) and a poor prognosis of primary breast cancer patients. In the present study we investigated whether measurements of the uncomplexed fraction of TIMP-1 added prognostic information to that already obtained from total TIMP-1. We measured the uncomplexed fraction of TIMP-1, using a thoroughly validated ELISA specific for this fraction, in 341 tumor tissue extracts obtained from patients with primary breast cancer. These measurements were related to previously performed measurements of total TIMP-1 as well as to patient outcome. The observation time was 8.3 years (range, 7.3–11.3 years). During this period 136 patients died, and 153 patients experienced recurrence of disease. Cox regression analysis of recurrence-free survival (RFS) suggested that a score based on both uncomplexed and total TIMP-1, reflecting the tumor level of TIMP-1/MMP complexes, would be a more precise estimate of prognosis than total TIMP-1 alone. Univariate survival analysis showed a highly significant relationship between high values of the score and poor outcomes for RFS (p = 0.0002; hazard ratio = 2.7; 95% confidence interval, 1.5–4.8). Similar results were found for overall survival (p = 0.0001; hazard ratio = 3.3; 95% confidence interval, 1.8–6.3). Multivariate analysis of RFS and overall survival demonstrated that the score was significant including the classical prognostic factors used in breast cancer (p < 0.0001). The present study raises the hypothesis that it is the tumor level of TIMP-1/MMP complexes (i.e. activated matrix metalloproteinases) rather than TIMP-1 itself that determines prognosis, supporting the use of the combined score and not only total TIMP-1 in stratification of breast cancer patients.

§ To whom correspondence should be addressed. Tel.: 4535283749; Fax: 4535353514; E-mail: suw{at}kvl.dk


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