Epigenetics in Breast Cancer

What's New?

Yi Huang; Shweta Nayak; Rachel Jankowitz; Nancy E Davidson; Steffi Oesterreich

Disclosures

Breast Cancer Res. 2011;13(6):225 

In This Article

Abstract and Introduction

Abstract

Epigenetic changes are critical for development and progression of cancers, including breast cancer. Significant progress has been made in the basic understanding of how various epigenetic changes such as DNA methylation, histone modification, miRNA expression, and higher order chromatin structure affect gene expression. The present review will focus on methylation and demethylation of histones. While the acetylation of histones has been at the forefront of well-characterized post-translational modifications of histones, including the development of inhibitors targeting de-acetylating enzymes, the past few years have witnessed a dramatic increase in knowledge regarding the role of histone methylation/demethylation. This is an exciting and rapidly evolving area of research, with much promise for potential clinical intervention in several cancers including breast cancer. We also summarize efforts to identity DNA methylation signatures that could be prognostic and/or predictive markers in breast cancer, focusing on recent studies using genome-wide approaches. Finally, we briefly review the efforts made by both the National Institutes of Health Epigenome Project and The Cancer Genome Atlas, especially highlighting the study of breast cancer epigenetics, exciting technological advances, potential roadblocks, and future directions.

Introduction

While the term epigenetics is often used loosely, and sometimes in rather different ways, the term is generally considered to encompass changes in DNA methylation, histone modifications, miRNA expression, and nucleo-some positioning and higher order chromatin as epigenetic changes affecting gene regulation. Epigenetics was defined as a discipline more than 50 years ago, by CH Waddington, and originally described changes in the development of organisms that could not be explained by changes in DNA. Subsequently it became clear that epigenetic modifications play important roles in diseases, including breast cancer. There is thus a pressing need to understand the functional genome; that is, the changes defined by regulatory mechanisms overlaying the genetic structure.

Over the past few years there has been an explosion in studies of epigenetics in breast cancer, reflected by the exponential increase of published manuscripts (Figure 1). A PubMed search for the keywords 'epigenetic' and 'breast cancer' reveals that the first publication was in 1983. Progress was slow until approximately 10 years ago when the number of studies started to steadily increase, at least in part fueled by improved technologies. In the present review, we focus on recent advances in the understanding of histone methylation and demethylation, a relatively new area with promise for clinical translation. We also review recent studies that have utilized genome-wide technologies for the study of DNA methylation. Much progress has been made in the characterization of noncoding RNAs, and the effect of higher order chromatin structure on gene expression in breast cancer; however, these discoveries lie outside the scope of our review.

Figure 1.

Increased rate of publication in the area of epigenetics and breast cancer. Data are derived from a PubMed citation analysis searching for 'breast cancer' and 'epigenetics', and are approximate reflections of the number of epigenetic studies in the breast cancer area.

Finally, we also discuss the relatively slow translation of results from the epigenetic field into the clinic. Although there has been a dramatic increase of research into the epigenetics of breast cancer and milestone discoveries have undoubtedly been made, the application of such findings into the clinical setting has been slow. This is in contrast to other areas - for example, profiling of gene expression, where we have witnessed a revolution in the past 4 to 6 years, especially in the translation of the results into the development of US Food and Drug Administration-approved multigene prognostic assays. Why have we not yet seen any predictive/prognostic tests that involve the characterization of epigenetic changes? In a similar way, although a number of drugs targeting epigenetic changes have been tested, at this time no epigenetic drug has received US Food and Drug Administration approval in breast cancer treatment. Is this a result from a slower development of techniques used for epigenetic analysis? Or are there additional obstacles? In the present review article we discuss some barriers to more rapid translation of epigenetic studies in breast tumors into clinical practice, and discuss the efforts by the Epigenome Project and The Cancer Genome Atlas (TCGA) that are expected to bring dramatic progress in the near future.

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