title: 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.
abstract: 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.
authors.affiliation: The Finsen Laboratory, Rigshospitalet dept. 8621, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
authors.forename: Anne-Sofie
authors.initials: AS
authors.lastname: Schrohl
authors.forename: Ib Jarle
authors.initials: IJ
authors.lastname: Christensen
authors.forename: Anders N
authors.initials: AN
authors.lastname: Pedersen
authors.forename: Vibeke
authors.initials: V
authors.lastname: Jensen
authors.forename: Henning
authors.initials: H
authors.lastname: Mouridsen
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.forename: Nils
authors.initials: N
authors.lastname: Brunner
authors.forename: Mads Nikolaj
authors.initials: MN
authors.lastname: Holten-Andersen
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis*; D011379:Prognosis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis*
chemical_list: D014408:Biomarkers, Tumor; D017395:Plasminogen Activator Inhibitor 1; D019715:Tissue Inhibitor of Metalloproteinase-1