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 nodepositive. 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. Molecular & Cellular Proteomics 2:164 -172, 2003.The present use of adjuvant systemic therapy in patients with primary breast cancer is based on classical prognostic parameters (nodal status, tumor size, grade of malignancy, receptor status, and age) (1). However, a small proportion of patients who are not offered therapy will still experience recurrence of disease, i.e. these patients are undertreated. In addition, a large proportion of the patients who are offered systemic therapy would have remained free of recurrence even without that therapy, i.e. these patients are overtreated. To optimize the use of adjuvant systemic therapy an improvement in the methods for identification of patients at risk of developing recurrence is needed.Proteolytic enzymes, their receptors, and their inhibitors are all important in the processes of cancer invasion and metastasis. In the urokinase-type plasminogen activator (uPA) 1 system, the serine protease uPA mediates localized activation of plasminogen with subsequent generation of plasmin. Proteolysis mediated by plasmin then is involved in several proFrom ‡The Finsen Laboratory, Rigshospitalet dept. 8621, Strandboulevarden 49, DK-2100 Copenhagen, Denmark, the §Institute for...

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The lack of correlation between tumour tissue TIMP-1 and blood levels of TIMP-1 suggests that other sources than the tumour tissue itself may contribute to the increased levels of plasma TIMP-1 in patients with colorectal cancer. However, degradation of cell membranes, rapid secretion into the blood stream and other factors may be responsible for the observed lack of association between TIMP-1 concentrations in blood and tumour tissue extracts.

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. Molecular & Cellular Proteomics 4:483-491, 2005.

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