The epigenetics of breast cancer - Opportunities for diagnostics, risk stratification and therapy

Abstract

The stage and molecular pathology-dependent prognosis of breast cancer, the limited treatment options for triple-negative carcinomas, as well as the development of resistance to therapies illustrate the need for improved early diagnosis and the development of new therapeutic approaches. Increasing data suggests that some answers to these challenges could be found in the area of epigenetics. In this study, we focus on the current research of the epigenetics of breast cancer, especially on the potential of epigenetics for clinical application in diagnostics, risk stratification and therapy. The differential DNA methylation status of specific gene regions has been used in the past to differentiate breast cancer cells from normal tissue. New technologies as detection of circulating nucleic acids including microRNAs to early detect breast cancer are emerging. Pattern of DNA methylation and expression of histone-modifying enzymes have been successfully used for risk stratification. However, all these epigenetic biomarkers should be validated in larger clinical studies. Recent preclinical and clinical studies show a therapeutic benefit of epigenetically active drugs for breast cancer entities that are still difficult to treat (triple negative, UICC stage IV). Remarkably, epigenetic therapies combined with chemotherapies or hormone-based therapies represent the most promising strategy. At the current stage, the integration of epigenetic substances into established breast cancer therapy protocols seems to hold the greatest potential for a clinical application of epigenetic research.

Keywords: DNA methylation; Epigenetic; breast cancer; histone acetylation; histone methylation.

Figure 1.

Schematic representation of main epigenetic targets for therapy in breast cancer. (a) DNA methyltransferases (DNMTs), mainly DNMT1, induce methylation in CpG dinucleotides (black circles), which silences gene expression through recruitment of methyl-binding proteins. DNMT inhibitors (DNMTis) as decitabine and 5-azacytidine are incorporated in the DNA and block DNMT activity. Depletion of DNMTs results in demethylation of CpG dinucleotides (white circles) and de-repression of gene expression. (b) Histone deacetyltransferases (HDACs) removes acetyl groups from histone tails resulting in compacted chromatin and gene repression. HDAC inhibitors (HDACis) inhibits HDACs and resulting in histone acetylation and de-repression of gene expression. (c) The histone methyltransferase (HMT) EZH2 induces methylation of H3K27 in histone tails, which repress gene expression of target genes. HMT inhibitors (HMTis) block EZH2, decreasing H3K27 methylation and activation of gene expression. (d) The histone demethyltransferase (HDM) LSD1 has a dual effect on controlling gene expression: decreases methylation of H3K9 activating gene expression and decreases methylation of H3K4 resulting in gene repression. Depending which histone mark dominates in the nucleosome, gene expression is activated or repressed. HDM inhibitors (HDMis) block LSD1 activity reverting these histone changes.

Figure 2.

Vorinostat increases the effect of established anti-tumour substances by opening chromatin. The loosening of the chromatin structure mediated by Vorinostat increases the accessibility for later applied substances (Kim et al. 2003). Pre-clinical as well as clinical studies have shown an associated increase in the anti-tumoural effect of various chemotherapeutic substances.

Figure 3.

EZH2 plays a crucial role in various epigenetic signalling pathways of breast cancer. (1) EZH2-mediated histone methylation, in cooperation with DNMTs, inhibits the function of the oestrogen receptor alpha by transcriptional silencing of the co-factor GREB1, which in turn leads to a decrease in cellular sensitivity to endocrine substances (Wu et al. 2018). (2) EZH2 modification by PARP1, triggered by cellular stress, reduces its methylation capacity and thus its oncogenic function. PARP inhibition can reverse this process and thus reactivate the oncogenic function of EZH2 in contrast to the primary therapeutic goal (Yamaguchi et al. 2018). Targeted EZH2 inhibition could intervene in both signalling pathways and thus represents a potential therapeutic approach.