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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0412-z) contains supplementary material, which is available to authorized users.
Highlights
Cells in one organism generally contain the same genetic information but present very different gene expression profiles
DNA methylation and histone modification signatures, especially those on promoter regions of genes, are well known to be associated with gene expression
DNA methylation, the first identified epigenetic modification, is written by a family of DNA methyltransferases (DNMTs). It occurs on carbon 5 of the cytosine mostly in the context of the dinucleotide cytosine phosphate guanine; it is classically known that the DNA methylation status of promoter regions is inversely correlated with gene expression [2]
Summary
Cells in one organism generally contain the same genetic information but present very different gene expression profiles. In a phase I/II study in 54 patients with metastatic breast cancer, vorinostat 200 to 300 mg twice daily on days 1 to 3, 8 to 10, and 15 to 17 was added to paclitaxel plus bevacizumab [60] This combination resulted in a 49% objective response rate (partial + complete remission) and 78% clinical benefit rate (objective response + stable disease >6 months). Expected epigenetic changes, such as decreased tumor DNA methylation [41], increased histone acetylation [60], and upregulation of gene expression [58], are observed after their administration in clinical breast cancer studies.
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