Epigenetic Therapy in Breast Cancer

Division of Hematology and Oncology, Comprehensive Cancer Center, The Ohio State University Medical Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA.
Current Breast Cancer Reports 03/2011; 3(1):34-43. DOI: 10.1007/s12609-010-0034-0
Source: PubMed


Breast carcinogenesis is a multistep process involving both genetic and epigenetic changes. Epigenetics is defined as reversible changes in gene expression, not accompanied by alteration in gene sequence. DNA methylation, histone modification, and nucleosome remodeling are the major epigenetic changes that are dysregulated in breast cancer. Several genes involved in proliferation, anti-apoptosis, invasion, and metastasis have been shown to undergo epigenetic changes in breast cancer. Because epigenetic changes are potentially reversible processes, much effort has been directed toward understanding this mechanism with the goal of finding effective therapies that target these changes. Both demethylating agents and the histone deacetylase inhibitors (HDACi) are under investigation as single agents or in combination with other systemic therapies in the treatment of breast cancer. In this review, we discuss the role of epigenetic regulation in breast cancer, in particular focusing on the clinical trials using therapies that modulate epigenetic mechanisms.

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    • "Despite growing advances in targeted therapies and screening techniques, breast cancer remains a leading cause of malignant mortality in women[1]. The onset and progression of breast cancer involve both genetic and epigenetic changes, and the latter are potentially reversible processes[2]. Histone deacetylase inhibitors (HDACIs), either alone or in combination with other agents, have consistently shown promise in clinical trials in the treatment of breast cancer[3]. "
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    ABSTRACT: Histone deacetylase inhibitors (HDACIs)-based therapies have stimulated interest via their anti-tumor activities, including apoptosis induction, cell cycle arrest, cell differentiation, and autophagy. However, the mechanisms of HDACI-associated anti-tumor activity are not yet clearly defined. The aim of this study was to explore the key events of Trichostatin A (TSA), a classic HDACI agent, against breast cancer cells. The MCF-7, MDA-MB-231 and MCF-10A cell lines were evaluated with colony-forming and cell viability assays. Apoptosis and cell cycle distribution were detected by flow cytometry. Mitochondrial function was measured with biochemical assays, flow cytometry and transmission electron microscopy. TSA inhibited breast cancer cell viability and proliferation, without affecting MCF-10A cell. TSA-induced breast cancer cell apoptosis was initiated by G2-M arrest and depended on mitochondrial reactive oxygen species (ROS) produced subsequent to reduced mitochondrial respiratory chain activity. The enhanced mitochondrial ROS production and apoptosis in cancer cells were markedly attenuated by antioxidants, such as N-acetyl cysteine (NAC), reduced glutathione (GSH) and Vitamin C. The present study demonstrated that TSA-induced cell death by arresting cell cycle in G2-M phase and was dependent on production of mitochondria-derived ROS, which was derived from impaired mitochondrial respiratory chain.
    PLoS ONE 03/2014; 9(3):e91610. DOI:10.1371/journal.pone.0091610 · 3.23 Impact Factor
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    ABSTRACT: Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre-clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of small-molecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives.
    Current pharmaceutical design 09/2012; 19(4). DOI:10.2174/138161213804581918 · 3.45 Impact Factor
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    ABSTRACT: The importance of epigenetic alterations such as DNA methylation, histone modification and nucleosome remodeling in breast cancer is well established. Epigenetic alterations are reversible, and much research has been focused on understanding these alterations with the aim of developing effective therapies. Prostate-derived Ets factor (PDEF) is a member of the Ets family of transcription factors and has long been under investigation for its key role in tumor development and progression. To date, no studies have been conducted to elucidate the epigenetic modifications of PDEF in cancer progression. Using breast and prostate cancer cells, we investigated the effect of the methylation inhibitor 5' azacytidine (AZA) on the expression of PDEF in these cells. The inhibition of methylation observed was specific to breast cancer cells as experiments with prostate cells did not exhibit any significant change. Notably, the expression of p21, a cyclin-dependent kinase (CDK) inhibitor 1 and also a target gene of PDEF, was found to be positively correlated with PDEF expression following 5'AZA treatment. Inhibition of methylation led to a decrease in the proliferation rate of MDA-MB-468 cells as revealed by MTT proliferation assay. Other epigenetic alterations such as histone modifications were not observed in these breast cancer cells following treatment with specific HDAC inhibitors. Our data suggest the possibility of epigenetic modification of PDEF due to DNA methylation and involvement of the cell cycle inhibitor p21. Future studies on the epigenetic alterations of PDEF in correlation with p21 or other targets may facilitate the development of effective therapies for the treatment of breast cancer.
    Oncology Reports 08/2013; 30(4). DOI:10.3892/or.2013.2661 · 2.30 Impact Factor
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