title: Measurement of the uncomplexed fraction of tissue inhibitor of metalloproteinases-1 in the prognostic evaluation of primary breast cancer patients.
abstract: 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.
authors.affiliation: Department of Veterinary Pathobiology, The Royal Veterinary and Agricultural University, Ridebanevej 9, DK-1870 Frederiksberg C.
authors.forename: Sidse Ørnbjerg
authors.initials: SØ
authors.lastname: Würtz
authors.forename: Ib Jarle
authors.initials: IJ
authors.lastname: Christensen
authors.forename: Anne-Sofie
authors.initials: AS
authors.lastname: Schrohl
authors.forename: Henning
authors.initials: H
authors.lastname: Mouridsen
authors.forename: Ulrik
authors.initials: U
authors.lastname: Lademann
authors.forename: Vibeke
authors.initials: V
authors.lastname: Jensen
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
mesh_terms: D001943:Breast Neoplasms / Q000175:diagnosis* / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D003718:Denmark; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000201:enzymology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012044:Regression Analysis; D015203:Reproducibility of Results; D012189:Retrospective Studies; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis* / Q000378:metabolism
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1