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

ABSTRACT 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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    ABSTRACT: The estrogen receptor (ER) pathway plays a critical role in breast cancer development and progression. Endocrine therapy targeting estrogen action is the most important systemic therapy for ER positive breast cancer. However its efficacy is limited by intrinsic and acquired resistance. Mechanisms responsible for endocrine resistance include deregulation of the ER pathway itself, including loss of ER expression, post-translational modification of ER, deregulation of ER co-activators; increased receptor tyrosine kinase signaling leading to activation of various intracellular pathways involved in signal transduction, proliferation and cell survival, including growth factor receptor tyrosine kinases human epidermal growth factor receptor-2, epidermal growth factor receptor, PI3K/AKT/mammalian target of rapamycin (mTOR), Mitogen activated kinase (MAPK)/ERK, fibroblast growth factor receptor, insulin-like growth factor-1 receptor; alterations in cell cycle and apoptotic machinery; Epigenetic modification including dysregulation of DNA methylation, histone modification, and nucleosome remodeling; and altered expression of specific microRNAs. Functional genomics has helped us identify a catalog of genetic and epigenetic alterations that may be exploited as potential therapeutic targets and biomarkers of response. New treatment combinations targeting ER and such oncogenic signaling pathways which block the crosstalk between these pathways have been proven effective in preclinical models. Results of recent clinical studies suggest that subsets of patients benefit from the combination of inhibitor targeting certain oncogenic signaling pathway with endocrine therapy. Especially, inhibition of the mTOR signaling pathway, a key component implicated in mediating multiple signaling cascades, offers a promising approach to restore sensitivity to endocrine therapy in breast cancer. We systematically reviewed important publications cited in PubMed, recent abstracts from ASCO annual meetings and San Antonio Breast Cancer Symposium, and relevant trials registered at We present the molecular mechanisms contributing to endocrine resistance, in particular focusing on the biological rationale for the clinical development of novel targeted agents in endocrine resistant breast cancer. We summarize clinical trials utilizing novel strategies to overcome therapeutic resistance, highlighting the need to better identify the appropriate patients whose diseases are most likely to benefit from these specific strategies.
    08/2014; 5(3):248-262. DOI:10.5306/wjco.v5.i3.248
  • Edited by Karina Martinez-Mayorga, José Luis Medina-Franco, 01/2014; Springer., ISBN: 978-3-319-10225-2
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    ABSTRACT: Nowadays, the mechanisms governing the occurrence of cancer are thought to be the consequence not only of genetic defects but also of epigenetic modifications. Therefore epigenetic has become a very attractive and increasingly investigated field of research in order to find new ways of prevention and treatment of neoplasia, and this is particularly the case for breast cancer (BC). Thus, this review will first develop the main known epigenetic modifications that can occur in cancer and then exposes the future role that control of epigenetic modifications might play in prevention, prognostication, follow-up and treatment of BC. Indeed, epigenetic biomarkers found in peripheral blood might become new tools to detect BC, to define its prognostic and to predict its outcome, whereas epi-drugs might have an increasing potential of development in the next future. However, if DNA Methyltransferase Inhibitors (DNMTi) and Histone Desacetylase Inhibitors (HDACi) have shown encouraging results in BC, their action remains non-specific. Thus, additional clinical studies are needed to evaluate more precisely the effects of these molecules, even if they have provided encouraging results in co-treatment and combined therapies. This review will also deal with the potential of RNA interference (RNAi) as epi-drugs. Finally, we will focus on the potential prevention of BC through epigenetic based on diet and we will particularly develop the possible place of Isothiocyanates (ITCs) from cruciferous vegetables or of Genistein (GE) from soybean in a dietary program that might potentially reduce the risk of BC in large populations. This article is protected by copyright. All rights reserved.
    International Journal of Cancer 11/2014; DOI:10.1002/ijc.29347 · 5.01 Impact Factor


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