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      Epigenetic Reprogramming of TGF-β Signaling in Breast Cancer

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          Abstract

          The Transforming Growth Factor-β (TGF-β) signaling pathway has a well-documented, context-dependent role in breast cancer development. In normal and premalignant cells, it acts as a tumor suppressor. By contrast, during the malignant phases of breast cancer progression, the TGF-β signaling pathway elicits tumor promoting effects particularly by driving the epithelial to mesenchymal transition (EMT), which enhances tumor cell migration, invasion and ultimately metastasis to distant organs. The molecular and cellular mechanisms that govern this dual capacity are being uncovered at multiple molecular levels. This review will focus on recent advances relating to how epigenetic changes such as acetylation and methylation control the outcome of TGF-β signaling and alter the fate of breast cancer cells. In addition, we will highlight how this knowledge can be further exploited to curb tumorigenesis by selective targeting of the TGF-β signaling pathway.

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          Most cited references60

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          Role of TET enzymes in DNA methylation, development, and cancer

          Ten eleven translocation (TET) genes, and especially TET2, are frequently mutated in various cancers, but how the TET proteins contribute to the onset and maintenance of these malignancies is largely unknown. In this review, Rasmussen and Helin highlight recent advances in understanding the physiological function of the TET proteins and their role in regulating DNA methylation and transcription. The pattern of DNA methylation at cytosine bases in the genome is tightly linked to gene expression, and DNA methylation abnormalities are often observed in diseases. The ten eleven translocation (TET) enzymes oxidize 5-methylcytosines (5mCs) and promote locus-specific reversal of DNA methylation. TET genes, and especially TET2 , are frequently mutated in various cancers, but how the TET proteins contribute to prevent the onset and maintenance of these malignancies is largely unknown. Here, we highlight recent advances in understanding the physiological function of the TET proteins and their role in regulating DNA methylation and transcription. In addition, we discuss some of the key outstanding questions in the field.
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            DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.

            About 90 percent of human pancreatic carcinomas show allelic loss at chromosome 18q. To identify candidate tumor suppressor genes on 18q, a panel of pancreatic carcinomas were analyzed for convergent sites of homozygous deletion. Twenty-five of 84 tumors had homozygous deletions at 18q21.1, a site that excludes DCC (a candidate suppressor gene for colorectal cancer) and includes DPC4, a gene similar in sequence to a Drosophila melanogaster gene (Mad) implicated in a transforming growth factor-beta (TGF-beta)-like signaling pathway. Potentially inactivating mutations in DPC4 were identified in six of 27 pancreatic carcinomas that did not have homozygous deletions at 18q21.1. These results identify DPC4 as a candidate tumor suppressor gene whose inactivation may play a role in pancreatic and possibly other human cancers.
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              Histone acetyltransferase complexes: one size doesn't fit all.

              Over the past 10 years, the study of histone acetyltransferases (HATs) has advanced significantly, and a number of HATs have been isolated from various organisms. It emerged that HATs are highly diverse and generally contain multiple subunits. The functions of the catalytic subunit depend largely on the context of the other subunits in the complex. We are just beginning to understand the specialized roles of HAT complexes in chromosome decondensation, DNA-damage repair and the modification of non-histone substrates, as well as their role in the broader epigenetic landscape, including the role of protein domains within HAT complexes and the dynamic interplay between HAT complexes and existing histone modifications.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                24 May 2019
                May 2019
                : 11
                : 5
                : 726
                Affiliations
                Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; s.suriyamurthy@ 123456lumc.nl (S.S.); d.a.baker@ 123456lumc.nl (D.B.); p.ten_dijke@ 123456lumc.nl (P.t.D.)
                Author notes
                [* ]Correspondence: p.v.iyengar@ 123456lumc.nl
                Author information
                https://orcid.org/0000-0003-0751-519X
                https://orcid.org/0000-0002-6495-137X
                Article
                cancers-11-00726
                10.3390/cancers11050726
                6563130
                31137748
                28a5babd-f41d-4cd3-a1e1-5eb65c266b98
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 27 March 2019
                : 22 May 2019
                Categories
                Review

                breast cancer,epigenetics,epithelial to mesenchymal transition,signal transduction,smad,tgf-β

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