Breast Cancer Epigenetics: From DNA Methylation to microRNAs

Abstract

Both appropriate DNA methylation and histone modifications play a crucial role in the maintenance of normal cell function and cellular identity. In cancerous cells these “epigenetic belts” become massively perturbed, leading to significant changes in expression profiles which confer advantage to the development of a malignant phenotype. DNA (cytosine-5)-methyltransferase 1 (Dnmt1), Dnmt3a and Dnmt3b are the enzymes responsible for setting up and maintaining DNA methylation patterns in eukaryotic cells. Intriguingly, DNMTs were found to be overexpressed in cancerous cells, which is believed to partly explain the hypermethylation phenomenon commonly observed in tumors. However, several lines of evidence indicate that further layers of gene regulation are critical coordinators of DNMT expression, catalytic activity and target specificity. Splice variants of DNMT transcripts have been detected which seem to modulate methyltransferase activity. Also, the DNMT mRNA 3′UTR as well as the coding sequence harbors multiple binding sites for trans-acting factors guiding post-transcriptional regulation and transcript stabilization. Moreover, microRNAs targeting DNMT transcripts have recently been discovered in normal cells, yet expression of these microRNAs was found to be diminished in breast cancer tissues. In this review we summarize the current knowledge on mechanisms which potentially lead to the establishment of a DNA hypermethylome in cancer cells.

DNA Methylation Changes Correlate with Gleason Score and Tumor Stage in Prostate Cancer

“…DNA methylation is a widely recognized epigenetic mark and it has been associated with prognosis for many malignancies (Deng et al, 2010;Veeck and Esteller, 2010). One of the epigenetic mechanisms involved in cancer progression is the silencing of relevant tumor suppressor genes by hypermethylation of their promoter regions.…”

Base Excision Repair Manipulation in Breast Carcinoma: A Prospective Avenue to Potentiate Genome Insulting Approach

“…In recent, data accumulated from genomic approaches point out that several miRNAs are deregulated in breast cancer [61,62]. Besides, a player involved in the miRNA maturation as endoribonuclease Dicer is also reported to be down regulated in breast carcinoma [61,62]. The Gadd45a (growth arrest and DNA-damage-inducible protein 45 alpha) is reported as nuclear protein to maintain genomic stability, DNA repair, cell growth retardation and DNA demethylation.…”

Dysregulation of Wnt Signaling in Breast Cancer

“…Epigenetic silencing of genes occurs via hypermethylation of CpG dinucleotides in promoter regions of genes or histone modifications (Veeck and Esteller, 2010). For example, sFRP1 mRNA is absent in invasive breast carcinomas (Suzuki et al, 2008;Ugolini et al, 1999Ugolini et al, , 2001.…”