Tumor progression and metastasis contribute to the great majority of breast cancer deaths. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are thought to be involved in tumor progression and metastasis. Thus, we determined whether the expression of MMP-9 and TIMP-1 is associated with prognosis in breast cancer patients. We measured serum MMP-9 and TIMP-1 by enzyme-linked immunosorbent assay in 60 breast cancer patients, 18 benign breast disease patients and 15 healthy controls. We also evaluated the expression of MMP-9 and TIMP-1 protein and mRNA in paraffin-embedded tumor tissues from the 60 breast cancer patients by immunohistochemistry and in situ hybridization. We then correlated serum and tissue levels of MMP-9 and TIMP-1 in breast cancer samples and their expression with patients' clinicopathologic characteristics. We found that serum levels of MMP-9 and TIMP-1 were significantly higher in breast cancer patients than in benign breast disease and in healthy controls. High serum levels of MMP-9 and TIMP-1 were associated with lymph node metastasis, higher tumor stage and lower relapse-free and overall survival (OS) rates. Compared to low expression, high tissue expression of MMP-9 protein was associated with lymph node metastasis and higher tumor stage; and high tissue expression of TIMP-1 was associated with a lower OS rate. Our findings suggest that MMP-9 and TIMP-1 may further be evaluated as biomarkers for predicting progression and prognosis of breast cancer. ' 2008 Wiley-Liss, Inc.Key words: MMP-9; TIMP-1; breast cancer; serum biomarker; patient survival Breast cancer is one of the most common neoplasias in women worldwide. However, despite considerable diagnostic and therapeutic advances in recent years, it is still the most common cause of cancer death in women aged 40-49 years in the United States. 1 Approximately 40% of patients with localized breast cancer have micrometastatic disease that is difficult to detect at the time of diagnosis and treatment (especially during adjunctive therapy after surgery) and results in disease recurrence and death several years after diagnosis. 2-4 Serum biomarkers would be valuable in the early diagnosis of breast cancer; they would also be useful to clinicians in detecting micrometastasis and determining the risk of recurrence. This information would also help clinicians determine suitable therapy.Matrix metalloproteinases (MMPs) are a large family of highly homologous, zinc-and calcium-dependent extracellular enzymes that can be loosely categorized as matrilysin, gelatinases, stromelysin, collagenases or membrane-type MMPs on the basis of substrate specificity, protein domain structure, sequence homologic characteristics and ability to be secreted. 5-7 MMP-9 is one of the 2 gelatinases that has been implicated in tumor cell invasion and metastasis because of its unique ability to degrade Type IV collagen (a major component of the basement membrane) and other essential extracellular matrix components. 8,9 MMP-9 and its natural...
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