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 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...

Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer

“…Patient characteristics and pathological findings were registered by the Danish Breast Cancer Cooperative Group (DBCG). Clinicopathological characteristics of these patients have been described previously [9,19] and are summarized in Table 1.…”

“…Tissue inhibitor of metalloproteinases-1 (TIMP-1) has proven to be a promising marker in breast cancer carrying both prognostic [7][8][9][10][11] and, as shown more recently, predictive information [12][13][14][15]. For example, our laboratory has previously demonstrated that high primary tumor tissue levels of TIMP-1 were significantly associated with a poor response to the most frequently used chemotherapeutic drugs in metastatic breast cancer [14].…”

Clinicopathologic implications of tissue inhibitor of metalloproteinase-1-positive diffuse large B-cell lymphoma

“…41,42 Upregulation of TIMP-1 expression, at both mRNA and protein levels, has been demonstrated in several types of cancer, and has been associated with a poor prognosis in the cancer patients. [43][44][45][46][47] Given its original role of MMP inhibition, TIMP-1 has paradoxically emerged as a poor prognostic factor and serum marker for many epithelial cancers. 6,7 Thus, TIMP-1 is a multifunctional protein having growth promotion and antiapoptotic effects as well as MMP inhibitory functions.…”

Clinical Relevance of Matrix Metalloproteases and their Inhibitors in Breast Cancer

“…These findings may be due to both MMPs are related to tumor invasion and metastasis by their special capacity to degrade the type IV collagen found in BM [66], and to induce angiogenesis [42]. Likewise, other MMPs or TIMPs may be overexpressed and/or related to clinical outcome in breast cancer, such as MMP-7 [34], MMP-11 [34,60], MT1-MMP (MMP-14) [34,59,67], MMP-13 [68], TIMP-1 [34,[69][70][71][72][73] or TIMP-2 [34,[73][74][75], and also the genetic polymorphisms of these proteins may have an association with breast cancer risk, progression and survival [76]. Discordant data about the prognostic value of the above-mentioned MMPs have also been published, and in this way have been related to only a few prognostic factors [77,78] or shown to have no association with clinicopathological parameters in breast cancer [59,79,80].…”