The Mechanism of DNA Methylation and miRNA in Breast Cancer

Abstract

Breast cancer is the most prevalent cancer in the world. Currently, the main treatments for breast cancer are radiotherapy, chemotherapy, targeted therapy and surgery. The treatment measures for breast cancer depend on the molecular subtype. Thus, the exploration of the underlying molecular mechanisms and therapeutic targets for breast cancer remains a hotspot in research. In breast cancer, a high level of expression of DNMTs is highly correlated with poor prognosis, that is, the abnormal methylation of tumor suppressor genes usually promotes tumorigenesis and progression. MiRNAs, as non-coding RNAs, have been identified to play key roles in breast cancer. The aberrant methylation of miRNAs could lead to drug resistance during the aforementioned treatment. Therefore, the regulation of miRNA methylation might serve as a therapeutic target in breast cancer. In this paper, we reviewed studies on the regulatory mechanisms of miRNA and DNA methylation in breast cancer from the last decade, focusing on the promoter region of tumor suppressor miRNAs methylated by DNMTs and the highly expressed oncogenic miRNAs inhibited by DNMTs or activating TETs.

Keywords: DNA methylation; breast cancer; drug resistance; miRNA.

Figure 1

The regulatory mechanisms of miRNA and DNA methylation in breast cancer. A schematic involved in the biogenesis and function of miRNA. Genes of miRNAs are first transcribed by pol II as pri-miRNA. Then, this nascent pri-miRNA is cleaved and shortened by DROSHA and DGCR8 in the nucleus to produce pre-miRNA. The pre-miRNA is transports into the cytoplasm by Exp5, where it is processed, cleaved and modified by RNase III, Dicer/TRBP and AGO2 to generate miRNA duplexes. Finally, the double strand is dissociated into a single strand, and AGO-2 is connected with guide strand to form an RNA-induced silencing complex (miRNA:RISC). In addition, the DNMTs gene undergoes a series of complex processes of transcription and finally forms the mature mRNA. The methylation of miRNAs is usually regulated by DNMTs. In turn, miRNA:RISC pairs with its complimentary target sequence on the 3’-UTR of DNMTs mRNA in a perfect and imperfect manner to suppress the expression level of DNMTs, forming a regulatory loop between miRNA and DNMTs in BC development. Note: The arrows represent the steps involved in the biogenesis and functions of miRNAs.