Plasma levels of the MMP-9:TIMP-1 complex as prognostic biomarker in breast cancer: a retrospective study (original) (raw)
Related papers
International Journal of Cancer, 2003
Previously we determined that plasma MMP-9 activity was significantly elevated in breast cancer patients compared to benign mammary pathologies and healthy controls. Now we analyzed its potential usefulness in the follow-up and in the prognosis of these patients. MMP-9 activity was measured by gelatin quantitative zymography in the euglobulin plasma fraction of 46 breast cancer patients in a 38-month follow-up study. Blood samples were obtained before surgery (S1), 1 month after (S2) and every 3 months. The relapse-free survival (RFS) and overall survival (OS) analysis was performed along 56 months in 113 patients using the Kaplan-Meier curves and Cox analysis. In 63% of the S2 analyzed, MMP-9 decreased after surgery. In 44 patients evaluated during the adjuvant period who developed a complete response, MMP-9 decreased compared to their S1, whereas 2 patients showed an enhancement in correlation with lack of response. Further analysis indicated that in all patients who never showed evidence of recurrence, plasma MMP-9 activity remained low, but it increased 1 to 8 months preceding the clinical detection of progression in those patients who relapsed. Kaplan-Meier curves indicated that high levels of plasma MMP-9 activity at the moment of breast cancer diagnosis were associated with a worse OS rate. Cox analysis showed it was not associated with tumor stage or patient's age. Our results, which show a good correlation between plasma MMP-9 activity and the clinical status of each patient, suggest its usefulness as a marker both in the follow-up and in the prognosis of breast cancer patients.
The influence of MMP-14, TIMP-2 and MMP-2 expression on breast cancer prognosis
Breast cancer research : BCR, 2006
Matrix metalloproteinase (MMP)-2 is very active at degrading extracellular matrix. It is under the influence of an activator, membrane type 1 MMP (MMP-14), and the tissue inhibitor of metalloproteases (TIMP)-2. We hypothesized that the individual expression of these three markers or their balance may help to predict breast cancer prognosis. MMP-2, MMP-14 and TIMP-2 expression has been evaluated by 35S mRNA in situ hybridization on paraffin material of 539 breast cancers without distant metastasis at diagnosis and with a median follow-up of 9.2 years. MMP-2 and MMP-14 mRNA was detected primarily in reactive stromal cells whereas TIMP-2 mRNA was expressed by both stromal and cancer cells. Of the three molecules, an adjusted Cox model revealed that high MMP-14 mRNA (> or = 10% cells) alone predicted a significantly shorter overall survival (p = 0.031) when adjusted for clinical factors (tumor size and number of involved lymph nodes). Prognostic significance was lost when further adj...
Molecular & Cellular Proteomics, 2005
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.
Journal of Cellular and Molecular Medicine, 2006
The goal of our study was to analyse the prognostic values for some matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in breast cancer. We evaluated the activity and the expression levels of MMP-9, MMP-2, TIMP-1 and TIMP-2 in malignant versus benign fresh breast tumor extracts. For this purpose, gelatinzymography, immunoblotting and ELISA were used to analyse the activity and expression of MMPs and TIMPs. We found that MMP-9 expression level and activity are increased in malignant tumors. In addition, MMP-9/TIMP-1 and MMP-2/TIMP-2 ratio values obtained by us were significantly different in malignant tumors compared to benign tumors. We suggest that the abnormal MMP-9/TIMP-1 balance plays a role in the configuration of breast invasive carcinoma of no special type and also in tumor growth, while altered MMP-2/TIMP-2 ratio value could be associated with lymph node invasion and used as a prognostic marker in correlation with Nottingham Prognostic Index. Finally, we showed that in malignant tumors high expression of estrogen receptors is associated with enhanced activity of MMP-2 and increased bcl-2 levels, while high expression of progesterone receptors is correlated with low TIMP-1 protein levels.
Medical Oncology, 2011
The aim of this study was to analyse the expression of matrix metalloproteinase-2(MMP-2), matrix metalloproteinase-9 (MMP-9) and aminopeptidase APN/ CD13 in breast carcinoma samples, and their possible prognostic value in breast cancer patients. The expression of MMP-2, MMP-9 and APN/CD13 in tumor cells was analysed in 138 breast carcinomas by immunohistochemical staining of tumor cells using the semiquantitative method for the detection of cytoplasmic and membrane reaction in tumor cells as well as stromal cells positivity. MMP-2 was positive in tumor cells of 52.9% patients and in stromal cells of 74.6% patients, while MMP-9 positive tumor and stromal cells were found in 84.8 and 63.8% patients, respectively. Tumor cell APN/CD13 expression was found in 36.2% patients. Stromal cell MMP-2 expression correlated significantly with tumor size and neoangiogenesis. A positive correlation was also observed between tumor cell MMP-9 expression and hormone receptor status. Stromal cell coexpression of MMP-2/ MMP-9 correlated significantly with tumor size. APN/ CD13 expression in tumor cells significantly correlated with tumor type and neoangiogenesis. Overall survival was significantly shorter in patients with MMP-2, MMP-2/ MMP-9 positive tumor cells, and tended to be shorter in patients with APN/CD13 positive tumor cells. Coexpression of MMP-2/MMP-9 in tumor cells was an independent risk factor for patient survival (OD = 13.9). Our results suggest that MMP-2, MMP-9, APN/CD13 expression and MMP-2/MMP-9 coexpression in combination with other standard prognostic factors can serve as a poor prognostic factor in the evaluation of breast cancer prognosis.
Anticancer research
Matrix metalloproteinases (MMPs) are involved with tumour invasion and metastasis. Controversial data exists concerning the prognostic value of MMP-9 in breast carcinoma. We examined, here, whether the MMP-9 immunoreactive protein would correlate with--the prognosis in breast carcinoma treated with hormonal adjuvant therapy. The MMP-9 status was determined immunohistochemically from primary tumour specimens in 168 postmenopausal breast cancer patients with a locally advanced (N+) disease treated with antiestrogen for three years after the primary therapy. A positive immunostaining for MMP-9 was found in 61.3% of 168 primary tumours without any significant correlation to clinical stage, histology or hormone receptor status. MMP-9 immunoreactivity did not correlate with the survival when the entire study population was included in the analysis. There was, however, a compromised disease-free survival in a subgroup of patients presenting with an estrogen receptor-negative and MMP-9-posi...
Molecular & Cellular Proteomics, 2003
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.
Military Medical and Pharmaceutical Journal of Serbia, 2019
Background/Aim. Breast cancer is one of the most common malignancies among women all over the world. Tumor microenvironment represents one of the main regulators of tumorigenesis. We investigated the role of matrix metalloproteinases 9 (MMP-9) concentration in peritumoral tissue as a prognostic marker in the breast cancer patients. Methods. The ELISA test was used to determine a total MMP-9 concentration in carcinoma and peritumoral tissue sample in the patients with breast cancer. Comparison of MMP-9 protein expression with the clinicopathological parameters was evaluated. Results. Peritumoral tissue at 3 cm distance from the tumor produces more MMP-9 than the tumor itself. The ratio of concentrations of MMP-9 in the tumor and peritumoral tissue considerably changes in favor of peritumoral tissue with the increase of tumor size and the involvement of axillary lymph nodes. In N0 stage, the concentration ratio of MMP-9 in the tumor and peritumoral tissues was 1 : 1.44, but in the N2 stage, the ratio was 1 : 26.5. Conclusion. In patients with breast cancer even in an early stadium there is a change in MMP-9 concentration in peritumoral tissue. We can extract the group of patients at increased risk for the development of lymph node metastasis. A statistically significant difference between the concentrations of MMP-9 in the peritumoral tissue and cancer tissue exists only in case of metastatic disease not in MO stadium implying need for early detection of still unknown metastases in such patients.
International Journal of Cancer, 2006
Matrix metalloproteinase (MMP) 2 and 9 are involved in cancer invasion and metastasis, and increased levels occur in serum and plasma of breast cancer (BC) patients. It is, however, unclear whether changes in serum levels can be exploited for early detection or classification of patients into different risk/disease categories. In our study, we measured concentration and activity of MMP2/9 in sera of 345 donors classified as low risk (Gail score < 1.7), high risk (HR) (Gail score 1.7), benign disease or BC. Kruskal-Wallis and Mann-Whitney nonparametric tests showed that total-MMP2 concentration is higher in HR compared to control (p 5 0.012), benign (p 5 0.001) and cancer (p 5 0.007). Active MMP2 (aMMP2) concentration is higher in control than benign and cancer (p < 0.001, respectively). Total and aMMP9 concentrations are higher in cancer than benign (p < 0.001, p 5 0.002, respectively). Total-MMP2 and total-MMP9 activities are lower in control than benign (p < 0.001, p 5 0.002, respectively) and cancer (p < 0.001, respectively). Total-MMP2 and MMP9 activities are also higher in cancer than benign (p 5 0.004, p < 0.001) and HR (p 5 0.008, p 5 0.007, respectively). These results were not affected by age or inclusion/exclusion of donors with noninvasive cancer or atypical hyperplasia. Linear discriminant analysis revealed that HR donors are characterized by lower total-MMP2 and higher aMMP2. Overall group classification accuracy was 64.5%. Independent validation based on the leave-one-out cross validation approach gave an overall classification of 63%. Our study provides evidence supporting the potential role of serum MMP2/9 as biomarkers for breast disease classification. ' 2006 Wiley-Liss, Inc.