Changes in the methylation level of microRNA genes as a factor of breast cancer development and progression

Abstract

Background. Methylation, as an epigenetic mechanism for regulation of gene expression, is crucial for the genome stability. Normally, this process is characterized by the ability to silence the oncogene activity and to support the action of suppressor genes. MicroRNAs (miRNAs) are another key epigenetic regulator of gene expression. Aberrant methylation of CpG islands in promoter regions of the genes that code miRNAs is the most important oncogenic factor. Aim. To expand the spectrum of miRNA genes hypermethylated in breast cancer and to study their relationship with metastasis and immunohistochemical status of the tumor. Methods. MiRNA tumor suppressor genes were selected that changed their methylation level in breast cancer patients. Using the method of quantitative methylation-specific PCR, the methylation level of eight miRNA genes associated with breast cancer was studied on a representative set of 70 paired breast cancer samples: MIR107, MIR124-2, MIR1258, MIR130B, MIR137, MIR191, MIR203A, and MIR339. Results. The methylation level of the genes MIR-107, MIR124-2, MIR1258, MIR130B, MIR137, MIR339 was significantly higher in breast cancer tissue compared to normal breast tissue whereas for the gene MIR191, it was significantly lower. Also, the methylation levels of genes MIR107, MIR1258, MIR130B, MIR137, and MIR339 were significantly increased at stages III-IV (advanced) breast cancer; in large tumors, the methylation levels were increased for MIR107, MIR1258, MIR130B, MIR137, and MIR339; in poorly differentiated tumors, the methylation level was increased for MIR124-2; and in the presence of lymph node metastases, for MIR107, MIR1258, MIR-137, and MIR-339. Tumors not expressing the progesterone receptor (PR) had a higher methylation level of MIR137 and MIR339. Conclusion. The study determined new molecular indicators for breast cancer progression and identified biomarkers that may be used in the differential diagnosis of breast cancer molecular subtype.