Current and upcoming approaches to exploit the reversibility of epigenetic mutations in breast cancer

Fahimeh Falahi, Michel van Kruchten, Nadine Martinet, Geesiena Hospers, Marianne G. Rots*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

36 Citations (Scopus)
209 Downloads (Pure)

Abstract

DNA methylation and histone modifications are important epigenetic modifications associated with gene (dys) regulation. The epigenetic modifications are balanced by epigenetic enzymes, so-called writers and erasers, such as DNA (de)methylases and histone (de)acetylases. Aberrant epigenetic alterations have been associated with various diseases, including breast cancer. Since aberrant epigenetic modifications are potentially reversible, they might represent targets for breast cancer therapy. Indeed, several drugs have been designed to inhibit epigenetic enzymes (epi-drugs), thereby reversing epigenetic modifications. US Food and Drug Administration approval has been obtained for some epi-drugs for hematological malignancies. However, these drugs have had very modest anti-tumor efficacy in phase I and II clinical trials in breast cancer patients as monotherapy. Therefore, current clinical trials focus on the combination of epi-drugs with other therapies to enhance or restore the sensitivity to such therapies. This approach has yielded some promising results in early phase II trials. The disadvantage of epi-drugs, however, is genome-wide effects, which may cause unwanted upregulation of, for example, pro-metastatic genes. Development of gene-targeted epigenetic modifications (epigenetic editing) in breast cancer can provide a novel approach to prevent such unwanted events. In this context, identification of crucial epigenetic modifications regulating key genes in breast cancer is of critical importance. In this review, we first describe aberrant DNA methylation and histone modifications as two important classes of epigenetic mutations in breast cancer. Then we focus on the preclinical and clinical epigenetic-based therapies currently being explored for breast cancer. Finally, we describe epigenetic editing as a promising new approach for possible applications towards more targeted breast cancer treatment.

Original languageEnglish
Article number412
Number of pages11
JournalBreast cancer research
Volume16
Issue number4
DOIs
Publication statusPublished - 29-Jul-2014

Keywords

  • HISTONE DEACETYLASE INHIBITOR
  • PHASE-II TRIAL
  • SUBEROYLANILIDE HYDROXAMIC ACID
  • SOLID TUMOR MALIGNANCIES
  • T-CELL LYMPHOMA
  • DNA METHYLATION
  • VALPROIC ACID
  • HDAC INHIBITORS
  • TARGET GENES
  • VORINOSTAT

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