MicroRNAs play an important role in the regulation of expression of many genes involved in cancer pathogenesis. One of the causes of miRNA level deregulation in tumors is the methylation of CpG islands in the promoter regions of the genes that encode them. Hypermethylation may lead to the suppression of miRNA gene expression and, as a consequence, to a decrease in their inhibitory effect on target gene mRNAs. A search for new miRNA genes hypermethylated in breast cancer has been carried out in the present study. The methylation of five miRNA genes associated with breast cancer (miR-132, miR-1258, miR-107, miR-130b, miR-137) has been as studied using a representative set of 41 breast cancer samples by methylation-specific PCR. Three new genes, MIR-132, MIR-137 and MIR-1258, with a high frequency of hypermethylation (41, 37 and 34%, respectively) have been identified in breast cancer. The methylation of these genes in the breast tissues of ten donors without cancer pathology in anamnesis was only found in single cases. These results enable the involvement of three miRNAs (miR-132, miR-137, miR-1258) and the methylation of the genes that encode them in the pathogenesis of breast cancer to be suggested.

Changes in the levels of expression of proapoptotic genes APAF1 and DAPK1 and antiapoptotic gene BCL2 were studied by real time PCR in specimens of tumors and histologically intact tissue from 28 patients with breast cancer. The expression of APAF1 and DAPK1 was below the normal in the majority of tumor samples (p<0.05), while the level of BCL2 mRNA more often surpassed the normal (p<0.1). Study of the same sample of specimens by methylspecific PCR showed predominance of APAF1 and DAPK1 hypermethylation (p<0.05 and p<0.1, respectively) and more frequent hypomethylation of BCL2. A significant correlation between changes in the levels of expression and methylation (r=0.40-0.49; p<0.05) was detected for all three genes (APAF1, DAPK1, and BCL2). The results suggest that methylation play an important role in the regulation of these apoptosis system genes in breast cancer.

MicroRNA and methylation are important epigenetic mechanisms in the pathogenesis of cancer. The role of a group of microRNA hypermethylated genes in the pathogenesis of ovarian cancer was studied and their diagnostic and prognostic potential was evaluated. Studies on a representative sample of 54 ovarian cancer specimens with the use of methyl-specific PCR resulted in detection of five microRNA genes (MIR-9-1, MIR-9-3, MIR-107, MIR-1258, and MIR-130b) methylated in the majority of tumor specimens in comparison with paired specimens of histologically intact tissue (37-57% vs. 4-9%, p<0.01). Methylation of three genes (MIR-9-1, MIR-9-3, and MIR-130b) was significantly (p≤0.05) associated with the parameters of ovarian cancer progress (clinical stage, differentiation degree, tumor size, and presence of metastases). These findings attest to oncosuppressive role of the studied microRNA genes (MIR-9-1, MIR-9-3, MIR-107, MIR-1258, and MIR-130b) in the pathogenesis and progress of ovarian cancer and indicated their prognostic potential.

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