Abstract
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) substantially contribute to the regulation of intercellular interactions and thereby play a role in maintaining the tissue structure and function. We examined methylation of a subset of 5’-cytosine-phosphate-guanine-3’ (CpG) dinucleotides in promoter regions of the MMP2, MMP11, MMP14, MMP15, MMP16, MMP17, MMP21, MMP23B, MMP24, MMP25, MMP28, TIMP1, TIMP2, TIMP3, and TIMP4 genes by methylation-sensitive restriction enzyme digestion PCR. In our collection of 183 breast cancer samples, abnormal hypermethylation was observed for CpGs in MMP2, MMP23B, MMP24, MMP25, and MMP28 promoter regions. The non-methylated status of the examined CpGs in promoter regions of MMP2, MMP23B, MMP24, MMP25, and MMP28 in tumors was associated with low HER2 expression, while the group of samples with abnormal hypermethylation of at least two of these MMP genes was significantly enriched with HER2-positive tumors. Abnormal methylation of MMP24 and MMP25 was significantly associated with a CpG island hypermethylated breast cancer subtype discovered by genome-wide DNA bisulfite sequencing. Our results indicate that abnormal hypermethylation of at least several MMP genes promoters is a secondary event not directly functional in breast cancer (BC) pathogenesis. We suggest that it is elevated and/or ectopic expression, rather than methylation-driven silencing, that might link MMPs to tumorigenesis.
Highlights
Matrix metalloproteinases (MMPs) are a broad group of extracellular proteinases that hydrolyze the extracellular matrix proteins
We performed selective screening of methylation of 5’-cytosine-phosphate-guanine-3’ dinucleotides (CpGs) located in the promoter regions of MMPs and tissue inhibitors of MMPs (TIMPs) genes in DNA extracted from 183 surgical fresh-frozen samples of breast cancer (BC) and matched morphologically normal breast tissues, and six autopsy samples of normal breast tissues, as well as from five BC cell lines, by methylation-sensitive restriction enzyme digestion PCR (MSRE-PCR)
Breast cancer cell lines were analyzed alongside with the clinical samples in order to validate the results of our MSRE-PCR assays, and to provide reference information that can be reevaluated by other researchers
Summary
Matrix metalloproteinases (MMPs) are a broad group of extracellular proteinases that hydrolyze the extracellular matrix proteins. The roles that MMPs and TIMPs play in tissue development and function are the subject of intense research, and new data continuously become available in the field. To date, both protein families have been implicated in rheumatoid arthritis, osteoarthritis, parodontitis, autoimmune lesions of the skin, and instability of atherosclerotic plaques [3,4]. MMPs can play a role in invasion, angiogenesis, the formation of premetastatic tumor niches, and antitumor immunity [6,7]
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