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Abnormal Hypermethylation of CpG Dinucleotides in Promoter Regions of Matrix Metalloproteinases Genes in Breast Cancer and its Relation to Epigenomic Subtypes and HER2 Overexpression

1
Molecular Genetic Diagnostics Laboratory 2, Research Centre for Medical Genetics, Moskvorechie St 1, 115522 Moscow, Russia
2
Epigenetics Laboratory, Research Centre for Medical Genetics, Moskvorechie St 1, 115522 Moscow, Russia
3
Medical Genetics Laboratory, I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya St 8-2, 119991 Moscow, Russia
4
Clinic of Personalized Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya St 8-2, 119991 Moscow, Russia
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VitaMed LLC, Seslavinskaya St 10, 121309 Moscow, Russia
6
Institute of Medicine, RUDN University, Miklukho-Maklaya St 6, 117198 Moscow, Russia
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Molecular Immunology Laboratory, Federal Scientific Clinical Centre of Pediatric Hematology Oncology Immunology Named after Dmitry Rogachev, Samory Mashela St 1, 117997 Moscow, Russia
8
Gene Therapy Laboratory, Institute of Gene Biology, Vavilova St 34/5, 119334 Moscow, Russia
*
Author to whom correspondence should be addressed.
Biomedicines 2020, 8(5), 116; https://doi.org/10.3390/biomedicines8050116
Received: 16 April 2020 / Revised: 6 May 2020 / Accepted: 8 May 2020 / Published: 10 May 2020
(This article belongs to the Special Issue Epigenetic Regulation of the Immune System)
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. View Full-Text
Keywords: matrix metalloproteinases; tissue inhibitors of matrix metalloproteinases; DNA methylation; breast cancer; methylation-sensitive restriction enzyme digestion PCR (MSRE-PCR); genome-wide DNA methylation analysis matrix metalloproteinases; tissue inhibitors of matrix metalloproteinases; DNA methylation; breast cancer; methylation-sensitive restriction enzyme digestion PCR (MSRE-PCR); genome-wide DNA methylation analysis
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Simonova, O.A.; Kuznetsova, E.B.; Tanas, A.S.; Rudenko, V.V.; Poddubskaya, E.V.; Kekeeva, T.V.; Trotsenko, I.D.; Larin, S.S.; Kutsev, S.I.; Zaletaev, D.V.; Nemtsova, M.V.; Strelnikov, V.V. Abnormal Hypermethylation of CpG Dinucleotides in Promoter Regions of Matrix Metalloproteinases Genes in Breast Cancer and its Relation to Epigenomic Subtypes and HER2 Overexpression. Biomedicines 2020, 8, 116.

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