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The overexpression membrane type 1 matrix metalloproteinase is associated with the progression and prognosis in breast cancer.

ABSTRACT: Membrane type 1 matrix metalloproteinase (MT1-MMP) has been demonstrated to play an important role in tumor progression. The aim of the present study was to analyze the expression of MT1-MMP in breast cancer and its correlation with clinicopathologic characteristics, including the survival of breast cancer patients. In our results, MT-MMP1 was up-expressed in breast cancer tissues compared with ductal hyperplasia tissues in microarray data (GSE2429). MT1-MMP mRNA and protein expression was markedly higher in breast cancer tissues than in normal breast tissues (P=0.005 and P=0.037, respectively). Using immunohistochemistry, high levels of MT1-MMP protein were positively correlated with the status of clinical stage (I-II vs. III-IV; P=0.043), lymph node metastasis (absence vs. presence; P=0.024), and distant metastasis (No vs. Yes; P=0.017) of breast cancer patients. Patients with higher MT1-MMP expression had a significantly shorter overall survival time than did patients with low MT1-MMP expression. Multivariate analysis indicated that the level of MT1-MMP expression was an independent prognostic indicator (P<0.001) for the survival of patients with breast cancer. In conclusions, MT1-MMP plays an important role on breast cancer aggressiveness and prognosis and may act as a promising target for prognostic prediction.

SUBMITTER: Li Y

PROVIDER: S-EPMC4346529 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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The overexpression membrane type 1 matrix metalloproteinase is associated with the progression and prognosis in breast cancer.

Li Yongping Y Cai Guohong G Yuan Shifang S Jun Yi Y Li Nanlin N Wang Ling L Chen Feng F Ling Rui R Yun Jun J

American journal of translational research 20150115 1

Membrane type 1 matrix metalloproteinase (MT1-MMP) has been demonstrated to play an important role in tumor progression. The aim of the present study was to analyze the expression of MT1-MMP in breast cancer and its correlation with clinicopathologic characteristics, including the survival of breast cancer patients. In our results, MT-MMP1 was up-expressed in breast cancer tissues compared with ductal hyperplasia tissues in microarray data (GSE2429). MT1-MMP mRNA and protein expression was marke ...[more]

PMID: 25755834

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Project description:Broad-spectrum matrix metalloproteinase (MMP) inhibitors (MMPI) were unsuccessful in cancer clinical trials, partly due to side effects resulting from limited knowledge of the full repertoire of MMP substrates, termed the substrate degradome, and hence the in vivo functions of MMPs. To gain further insight into the degradome of MMP-14 (membrane type 1 MMP) an MMPI, prinomastat (drug code AG3340), was used to reduce proteolytic processing and ectodomain shedding in human MDA-MB-231 breast cancer cells transfected with MMP-14. We report a quantitative proteomic evaluation of the targets and effects of the inhibitor in this cell-based system. Proteins in cell-conditioned medium (the secretome) and membrane fractions with levels that were modulated by the MMPI were identified by isotope-coded affinity tag (ICAT) labeling and tandem mass spectrometry. Comparisons of the expression of MMP-14 with that of a vector control resulted in increased MMP-14/vector ICAT ratios for many proteins in conditioned medium, indicating MMP-14-mediated ectodomain shedding. Following MMPI treatment, the MMPI/vehicle ICAT ratio was reversed, suggesting that MMP-14-mediated shedding of these proteins was blocked by the inhibitor. The reduction in shedding or the release of substrates from pericellular sites in the presence of the MMPI was frequently accompanied by the accumulation of the protein in the plasma membrane, as indicated by high MMPI/vehicle ICAT ratios. Considered together, this is a strong predictor of biologically relevant substrates cleaved in the cellular context that led to the identification of many undescribed MMP-14 substrates, 20 of which we validated biochemically, including DJ-1, galectin-1, Hsp90alpha, pentraxin 3, progranulin, Cyr61, peptidyl-prolyl cis-trans isomerase A, and dickkopf-1. Other proteins with altered levels, such as Kunitz-type protease inhibitor 1 and beta-2-microglobulin, were not substrates in biochemical assays, suggesting an indirect affect of the MMPI, which might be important in drug development as biomarkers or, in preclinical phases, to predict systemic drug actions and adverse side effects. Hence, this approach describes the dynamic pattern of cell membrane ectodomain shedding and its perturbation upon metalloproteinase drug treatment.

Dataset Information

The overexpression membrane type 1 matrix metalloproteinase is associated with the progression and prognosis in breast cancer.

Publications

The overexpression membrane type 1 matrix metalloproteinase is associated with the progression and prognosis in breast cancer.

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