The Epigenomic Revolution in Breast Cancer
2017; Elsevier BV; Volume: 187; Issue: 10 Linguagem: Inglês
10.1016/j.ajpath.2017.07.002
ISSN1525-2191
AutoresVerónica Dávalos, Anna Martínez‐Cardús, Manel Esteller,
Tópico(s)Histone Deacetylase Inhibitors Research
ResumoFrom the first identification of aberrant DNA methylation in primary tumors in humans more than 3 decades ago, progress in cancer epigenetics research has been exponential. For many years, cancer epigenetics studies relied on the identification of DNA methylation and histone modifications at specific genes. Those studies laid the foundation for the field and revealed the epigenetic alterations as hallmarks of cancer, as well as the crucial role of epigenetic mechanisms in tumorigenesis. The introduction of next-generation sequencing and array-based technologies for analyzing epigenetic states has accelerated our understanding about cancer and have become potent tools in our fight against the disease. Findings emerging from epigenome-wide analyses have led to new discoveries with remarkable clinical applications. This review summarizes the gene-specific epigenetic alterations common in breast cancer and discusses the recent advances in breast cancer epigenomics, focusing on their contribution to diagnosis, prognosis, patient stratification, and treatment of the disease. From the first identification of aberrant DNA methylation in primary tumors in humans more than 3 decades ago, progress in cancer epigenetics research has been exponential. For many years, cancer epigenetics studies relied on the identification of DNA methylation and histone modifications at specific genes. Those studies laid the foundation for the field and revealed the epigenetic alterations as hallmarks of cancer, as well as the crucial role of epigenetic mechanisms in tumorigenesis. The introduction of next-generation sequencing and array-based technologies for analyzing epigenetic states has accelerated our understanding about cancer and have become potent tools in our fight against the disease. Findings emerging from epigenome-wide analyses have led to new discoveries with remarkable clinical applications. This review summarizes the gene-specific epigenetic alterations common in breast cancer and discusses the recent advances in breast cancer epigenomics, focusing on their contribution to diagnosis, prognosis, patient stratification, and treatment of the disease. The term epigenetics was introduced by C.H. Waddington in 1942 to refer to the study of the processes by which genotype give rise to phenotype.1Waddington CH: The epigenotype. Endeavour 1942, 1:18–20.Google Scholar It was later redefined as those heritable changes in gene expression that do not involve changes in the underlying DNA sequence.2Holliday R. The inheritance of epigenetic defects.Science. 1987; 238: 163-170Crossref PubMed Google Scholar The most studied epigenetic modifications include DNA methylation and histone changes. These modifications modulate chromatin conformation and have crucial roles in the regulation of gene expression and in the accessibility of transcription factors, coactivators, and co-repressors. In humans, DNA methylation occurs at the carbon-5 of the cytosine in 5'-C-phosphate-G-3' (CpG) dinucleotides. This reaction is catalyzed by DNA methyltransferases (DNMTs). DNMTs 3a and 3b (de novo DNMTs) transfer a methyl group from S-adenosyl-methionine to previously unmethylated cytosines, whereas DNMT1 (maintenance DNMT) preserves the methylation patterns throughout each cell division. CpG sites are not randomly distributed in the genome, but instead there are CpG-rich zones known as CpG islands, located mainly at the regulatory regions in 40% to 60% of all genes.3Antequera F. Structure, function and evolution of CpG island promoters.Cell Mol Life Sci. 2003; 60: 1647-1658Crossref PubMed Scopus (0) Google Scholar, 4Esteller M. Epigenetics in cancer.N Engl J Med. 2008; 358: 1148-1159Crossref PubMed Scopus (2135) Google Scholar Methylation of CpG islands is a rare event in normal cells, restricted to untranscribed genes in the X chromosome, imprinted genes, germline genes, and some tissue-specific genes. However, CpG island hypermethylation is a common hallmark in cancer cells, first associated with tumor suppressor gene silencing.4Esteller M. Epigenetics in cancer.N Engl J Med. 2008; 358: 1148-1159Crossref PubMed Scopus (2135) Google Scholar Along with DNA methylation, histone modifications are the most studied epigenetic events related to cancer progression. Regulation of gene expression can occur through post-translational modifications of the histone tails, including covalent changes such as acetylation, methylation, phosphorylation, ubiquitination, SUMOylation (small ubiquitin-like modifiers), proline isomerization, and ADP-ribosylation. Their presence on histones form the so-called histone code, which dictates the chromatin structure in which DNA is packaged and can orchestrate the ordered recruitment of enzyme complexes to wrap the DNA.5Tessarz P. Kouzarides T. Histone core modifications regulating nucleosome structure and dynamics.Nat Rev Mol Cell Biol. 2014; 15: 703-708Crossref PubMed Scopus (218) Google Scholar, 6Kouzarides T. Chromatin modifications and their function.Cell. 2007; 128: 693-705Abstract Full Text Full Text PDF PubMed Scopus (5776) Google Scholar This histone code is written and erased by histone modifying enzymes. The writer of histone modification refers to an enzyme that catalyzes a chemical modification of histones in a residue-specific manner (ie, histone lysine methyltransferases or histone lysine acetyltransferases), and the eraser of histone marks refers to an enzyme that removes a chemical modification from histones [ie, histone lysine demethylases or histone lysine deacetylases (HDAC/KDAC)]. This code is interpreted by reader or effector proteins that specifically bind to a certain type or a combination of histone modifications and translate the histone code into a meaningful biological outcome, whether it is transcriptional activation or silencing, or other cellular responses. In addition to this recruitment mechanism, histone marks per se can modulate the chromatin conformation based on steric or charge interactions (ie, neutralization of the positive charges of histones by acetylation of lysines).5Tessarz P. Kouzarides T. Histone core modifications regulating nucleosome structure and dynamics.Nat Rev Mol Cell Biol. 2014; 15: 703-708Crossref PubMed Scopus (218) Google Scholar, 6Kouzarides T. Chromatin modifications and their function.Cell. 2007; 128: 693-705Abstract Full Text Full Text PDF PubMed Scopus (5776) Google Scholar, 7Chi P. Allis C.D. Wang G.G. Covalent histone modifications–miswritten, misinterpreted and mis-erased in human cancers.Nat Rev Cancer. 2010; 10: 457-469Crossref PubMed Scopus (0) Google Scholar Altogether, this complex epigenetic network guarantees dynamic and accurate control of gene expression. From the first identification of aberrant DNA methylation in primary human tumors more than 3 decades ago,8Feinberg A.P. Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts.Nature. 1983; 301: 89-92Crossref PubMed Scopus (1495) Google Scholar the epigenetics field has achieved a position as relevant as genetics in cancer research. Numerous studies identifying gene-specific epigenetic alterations that occur in cancer have revealed that in addition to genetic aberrations, epigenetic alterations are crucial players in cancer development and progression. In the past few years, the introduction of next-generation sequencing and array-based technologies has accelerated and expanded our knowledge about the relevance of epigenetic mechanisms in tumorigenesis. Moreover, the clinical applications of findings from epigenome-wide analyses are increasing. In this review, we provide an overview of gene-specific epigenetic alterations common in breast cancer and discuss the recent advances in breast cancer epigenomics, focusing on their contribution to diagnosis, prognosis, patient stratification, and treatment of the disease. Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer-related death among women worldwide. In United States, approximately 255,180 new cases of breast carcinoma will be diagnosed and 41,070 deaths will occur during 2017.9Valencia O.M. Samuel S.E. Viscusi R.K. Riall T.S. Neumayer L.A. Aziz H. The role of genetic testing in patients with breast cancer: a review.JAMA Surg. 2017; 152: 589-594Crossref PubMed Scopus (0) Google Scholar Gene expression profiling studies have classified breast cancers into subtypes with different prognostic behavior.10Pourteimoor V. Mohammadi-Yeganeh S. Paryan M. Breast cancer classification and prognostication through diverse systems along with recent emerging findings in this respect; the dawn of new perspectives in the clinical applications.Tumour Biol. 2016; 37: 14479-14499Crossref PubMed Scopus (0) Google Scholar Most breast tumors are characterized by the expression of estrogen receptor α (ESR1), progesterone receptor (PR), or human epidermal growth factor receptor 2 [HER2 (alias ERBB2)] proto-oncogene. Treatment with antiestrogens and agents targeting HER2 significantly improve survival in many of these cases.11Sonnenblick A. Piccart M. Adjuvant systemic therapy in breast cancer: quo vadis?.Ann Oncol. 2015; 26: 1629-1634Crossref PubMed Scopus (3) Google Scholar However, there is a subset of 15% to 25% of breast cancer cases that are negative for ESR1, PR, and HER2, called triple-negative breast cancers (TNBCs), in which chemotherapy-based schedules are the standard of care, in part due to the lack of target-specific therapies, making it the subtype associated with worse prognosis.11Sonnenblick A. Piccart M. Adjuvant systemic therapy in breast cancer: quo vadis?.Ann Oncol. 2015; 26: 1629-1634Crossref PubMed Scopus (3) Google Scholar Despite it being shown that hormone receptor positivity is predictive of response to antiestrogen treatment, 30% to 40% of patients develop resistance. The loss of estrogen receptor (ER) expression increases tumor aggressiveness and leads to failure of endocrine therapy.12Giacinti L. Claudio P.P. Lopez M. Giordano A. Epigenetic information and estrogen receptor alpha expression in breast cancer.Oncologist. 2006; 11: 1-8Crossref PubMed Scopus (0) Google Scholar Moreover, some tumors ER-positive (ER+) at the time of diagnosis become ER-negative (ER−) in the course of the clinical evolution of the disease. Interestingly, whereas hypermethylation of neither ESR1 nor PR seems to be a good predictor of its own receptor status, each is the best predictor of the status of the other receptor.13Widschwendter M. Siegmund K.D. Muller H.M. Fiegl H. Marth C. Muller-Holzner E. Jones P.A. Laird P.W. Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen.Cancer Res. 2004; 64: 3807-3813Crossref PubMed Scopus (0) Google Scholar, 14Gaudet M.M. Campan M. Figueroa J.D. Yang X.R. Lissowska J. Peplonska B. Brinton L.A. Rimm D.L. Laird P.W. Garcia-Closas M. Sherman M.E. DNA hypermethylation of ESR1 and PGR in breast cancer: pathologic and epidemiologic associations.Cancer Epidemiol Biomarkers Prev. 2009; 18: 3036-3043Crossref PubMed Scopus (40) Google Scholar Thus, a lack of methylation of ESR1 is associated with PR expression, as activated ER induces PR expression. Widschwendter et al13Widschwendter M. Siegmund K.D. Muller H.M. Fiegl H. Marth C. Muller-Holzner E. Jones P.A. Laird P.W. Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen.Cancer Res. 2004; 64: 3807-3813Crossref PubMed Scopus (0) Google Scholar found that ESR1 methylation is a good survival predictor only in tamoxifen-treated patients, whereas ARHI methylation predicts survival only in non–tamoxifen-treated patients. Moreover, they showed that CYP1B1 methylation predicts tamoxifen response. Additionally, Martínez-Galán et al15Martínez-Galán J. Torres-Torres B. Nunez M.I. Lopez-Penalver J. Del Moral R. Ruiz De Almodovar J.M. Menjon S. Concha A. Chamorro C. Rios S. Delgado J.R. ESR1 gene promoter region methylation in free circulating DNA and its correlation with estrogen receptor protein expression in tumor tissue in breast cancer patients.BMC Cancer. 2014; 14: 59Crossref PubMed Scopus (0) Google Scholar observed a significant correlation between the hypermethylation of ESR1 in the peripheral blood and lack of ER expression in excised tumor tissue. They suggested a prognostic role of ESR1 methylation status in the identification of luminal phenotypes with poor prognosis and potentially higher resistance to hormone treatment. Additionally, the direct relationship described between RASSF1A promoter methylation and the expression of ER could also add value in the prognosis of hormone therapy response.16Kajabova V. Smolkova B. Zmetakova I. Sebova K. Krivulcik T. Bella V. Kajo K. Machalekova K. Fridrichova I. RASSF1A promoter Methylation levels positively correlate with estrogen receptor expression in breast cancer patients.Transl Oncol. 2013; 6: 297-304Abstract Full Text PDF PubMed Scopus (0) Google Scholar On the other hand, triple-negative tumors, characterized by a lack of expression of ESR1, PR, and HER2, show an enrichment of alterations in DNA repair genes, mainly BRCA1.10Pourteimoor V. Mohammadi-Yeganeh S. Paryan M. Breast cancer classification and prognostication through diverse systems along with recent emerging findings in this respect; the dawn of new perspectives in the clinical applications.Tumour Biol. 2016; 37: 14479-14499Crossref PubMed Scopus (0) Google Scholar BRCA proteins 1 and 2 are involved in double-strand break repair through homologous recombination.17Li M.L. Greenberg R.A. Links between genome integrity and BRCA1 tumor suppression.Trends Biochem Sci. 2012; 37: 418-424Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Germline mutations in the BRCA genes may be involved in up to 30% of inherited breast carcinomas.9Valencia O.M. Samuel S.E. Viscusi R.K. Riall T.S. Neumayer L.A. Aziz H. The role of genetic testing in patients with breast cancer: a review.JAMA Surg. 2017; 152: 589-594Crossref PubMed Scopus (0) Google Scholar However, in sporadic disease, silencing of BRCA1 largely occurs by promoter hypermethylation, especially in the presence of loss of heterozygosity and in the triple-negative subgroup.18Esteller M. Silva J.M. Dominguez G. Bonilla F. Matias-Guiu X. Lerma E. Bussaglia E. Prat J. Harkes I.C. Repasky E.A. Gabrielson E. Schutte M. Baylin S.B. Herman J.G. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors.J Natl Cancer Inst. 2000; 92: 564-569Crossref PubMed Google Scholar, 19Veeck J. Ropero S. Setien F. Gonzalez-Suarez E. Osorio A. Benitez J. Herman J.G. Esteller M. BRCA1 CpG island hypermethylation predicts sensitivity to poly(adenosine diphosphate)-ribose polymerase inhibitors.J Clin Oncol. 2010; 28 (author reply e565–e566): e563-e564Crossref PubMed Scopus (0) Google Scholar These potentially lethal events in homologous recombination-deficient cells can be exploited for therapeutic purposes.17Li M.L. Greenberg R.A. Links between genome integrity and BRCA1 tumor suppression.Trends Biochem Sci. 2012; 37: 418-424Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 18Esteller M. Silva J.M. Dominguez G. Bonilla F. Matias-Guiu X. Lerma E. Bussaglia E. Prat J. Harkes I.C. Repasky E.A. Gabrielson E. Schutte M. Baylin S.B. Herman J.G. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors.J Natl Cancer Inst. 2000; 92: 564-569Crossref PubMed Google Scholar, 19Veeck J. Ropero S. Setien F. Gonzalez-Suarez E. Osorio A. Benitez J. Herman J.G. Esteller M. BRCA1 CpG island hypermethylation predicts sensitivity to poly(adenosine diphosphate)-ribose polymerase inhibitors.J Clin Oncol. 2010; 28 (author reply e565–e566): e563-e564Crossref PubMed Scopus (0) Google Scholar, 20Lord C.J. Ashworth A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers.Nat Med. 2013; 19: 1381-1388Crossref PubMed Scopus (166) Google Scholar For instance, the effect of BRCA1 hypermethylation in sensitivity to DNA-damaging chemotherapeutic agents such as cisplatin in TNBC patients has been described.21Stefansson O.A. Villanueva A. Vidal A. Marti L. Esteller M. BRCA1 epigenetic inactivation predicts sensitivity to platinum-based chemotherapy in breast and ovarian cancer.Epigenetics. 2012; 7: 1225-1229Crossref PubMed Scopus (53) Google Scholar Interestingly, Veeck et al19Veeck J. Ropero S. Setien F. Gonzalez-Suarez E. Osorio A. Benitez J. Herman J.G. Esteller M. BRCA1 CpG island hypermethylation predicts sensitivity to poly(adenosine diphosphate)-ribose polymerase inhibitors.J Clin Oncol. 2010; 28 (author reply e565–e566): e563-e564Crossref PubMed Scopus (0) Google Scholar demonstrated that BRCA1 promoter hypermethylation predicted sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors in nonhereditary TNBC, suggesting its inclusion in prospective clinical trials as a potential biomarker of sensitivity to these compounds. The mechanism through which BRCA1 methylation sensitizes tumors to PARP inhibitors is described in Figure 1. Nonetheless, BRCA1 re-expression with retained BRCA1 promoter hypermethylation has been detected in patient-derived xenografts of BRCA1-deficient breast cancer. De novo gene fusions place BRCA1 under the transcriptional control of a heterologous promoter, resulting in re-expression of BRCA1 and the acquisition of therapy resistance.22Ter Brugge P. Kristel P. van der Burg E. Boon U. de Maaker M. Lips E. Mulder L. de Ruiter J. Moutinho C. Gevensleben H. Marangoni E. Majewski I. Jozwiak K. Kloosterman W. van Roosmalen M. Duran K. Hogervorst F. Turner N. Esteller M. Cuppen E. Wesseling J. Jonkers J. Mechanisms of therapy resistance in patient-derived xenograft models of BRCA1-deficient breast cancer.J Natl Cancer Inst. 2016; 108Crossref PubMed Scopus (25) Google Scholar Furthermore, epigenetic alterations in cancer-related pathways in HER2+ breast cancers have also been identified, such as the activation of the wingless-type mouse mammary tumor virus integration site family (WNT) pathway by aberrant methylation of its negative regulators.23Yamaguchi T. Mukai H. Yamashita S. Fujii S. Ushijima T. Comprehensive DNA methylation and extensive mutation analyses of HER2-positive breast cancer.Oncology. 2015; 88: 377-384Crossref PubMed Scopus (4) Google Scholar Hypermethylation-mediated silencing of the genes encoding the WNT-negative regulators WIF1 and DKK3 has been reported in breast carcinogenesis.24Veeck J. Wild P.J. Fuchs T. Schuffler P.J. Hartmann A. Knuchel R. Dahl E. Prognostic relevance of Wnt-inhibitory factor-1 (WIF1) and Dickkopf-3 (DKK3) promoter methylation in human breast cancer.BMC Cancer. 2009; 9: 217Crossref PubMed Scopus (0) Google Scholar, 25Huang K.T. Mikeska T. Li J. Takano E.A. Millar E.K. Graham P.H. Boyle S.E. Campbell I.G. Speed T.P. Dobrovic A. Fox S.B. Assessment of DNA methylation profiling and copy number variation as indications of clonal relationship in ipsilateral and contralateral breast cancers to distinguish recurrent breast cancer from a second primary tumour.BMC Cancer. 2015; 15: 669Crossref PubMed Scopus (2) Google Scholar, 26Ai L. Tao Q. 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Dinis-Ribeiro M. Costa I. Costa V.L. Filipe L. Carvalho A.L. Hoque M.O. Pais I. Leal C. Teixeira M.R. Sidransky D. Quantitative hypermethylation of a small panel of genes augments the diagnostic accuracy in fine-needle aspirate washings of breast lesions.Breast Cancer Res Treat. 2008; 109: 27-34Crossref PubMed Scopus (0) Google Scholar described the potential roles of RASSF1A, CCND2, HIN1, and APC as diagnostic biomarkers, using quantitative methylation–specific PCR in fine-needle aspiration breast biopsies; other investigators have found that hypermethylation of RASSF1A, CCDN2, HIN1, and APC was correlated with hormone receptor (HR) + breast cancer phenotypes, with lower frequencies in ER and HER2 double-negative tumors.29Feng W. Shen L. Wen S. Rosen D.G. Jelinek J. Hu X. Huan S. Huang M. Liu J. Sahin A.A. Hunt K.K. Bast Jr., R.C. Shen Y. Issa J.P. Yu Y. Correlation between CpG methylation profiles and hormone receptor status in breast cancers.Breast Cancer Res. 2007; 9: R57Crossref PubMed Scopus (0) Google Scholar, 30Sunami E. Shinozaki M. Sim M.S. Nguyen S.L. Vu A.T. Giuliano A.E. Hoon D.S. Estrogen receptor and HER2/neu status affect epigenetic differences of tumor-related genes in primary breast tumors.Breast Cancer Res. 2008; 10: R46Crossref PubMed Scopus (0) Google Scholar Some reports have also shown that hypermethylation of CDH13 and GSTP1 occurs more frequently in triple-negative and lymph nodes–positive patients, respectively.13Widschwendter M. Siegmund K.D. Muller H.M. Fiegl H. Marth C. Muller-Holzner E. Jones P.A. Laird P.W. Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen.Cancer Res. 2004; 64: 3807-3813Crossref PubMed Scopus (0) Google Scholar, 29Feng W. Shen L. Wen S. Rosen D.G. Jelinek J. Hu X. Huan S. Huang M. Liu J. Sahin A.A. Hunt K.K. Bast Jr., R.C. Shen Y. Issa J.P. Yu Y. Correlation between CpG methylation profiles and hormone receptor status in breast cancers.Breast Cancer Res. 2007; 9: R57Crossref PubMed Scopus (0) Google Scholar, 30Sunami E. Shinozaki M. Sim M.S. Nguyen S.L. Vu A.T. Giuliano A.E. Hoon D.S. Estrogen receptor and HER2/neu status affect epigenetic differences of tumor-related genes in primary breast tumors.Breast Cancer Res. 2008; 10: R46Crossref PubMed Scopus (0) Google Scholar, 31Toyooka K.O. Toyooka S. Virmani A.K. Sathyanarayana U.G. Euhus D.M. Gilcrease M. Minna J.D. Gazdar A.F. Loss of expression and aberrant methylation of the CDH13 (H-cadherin) gene in breast and lung carcinomas.Cancer Res. 2001; 61: 4556-4560PubMed Google Scholar Radpour et al32Radpour R. Kohler C. Haghighi M.M. Fan A.X. Holzgreve W. Zhong X.Y. Methylation profiles of 22 candidate genes in breast cancer using high-throughput MALDI-TOF mass array.Oncogene. 2009; 28: 2969-2978Crossref PubMed Scopus (0) Google Scholar determined, by semiquantitative methylation changes through mass spectrometry–based techniques, a set of hypermethylated genes associated with breast carcinogenesis: In addition to the aforementioned BRCA1, APC, and GSTP1, they found BIN1, BMP6, ESR2, CDKN2A (p16), CDKN1A (p21), TIMP3, and CST6. Interestingly, hypermethylation of the CST6 promoter has also been detected in cell-free DNA, showing its value as a prognostic factor of relapse and of survival in operable breast cancer patients.33Chimonidou M. Tzitzira A. Strati A. Sotiropoulou G. Sfikas C. Malamos N. Georgoulias V. Lianidou E. CST6 promoter methylation in circulating cell-free DNA of breast cancer patients.Clin Biochem. 2013; 46: 235-240Crossref PubMed Scopus (36) Google Scholar Hypermethylation of other gene promoters detected in circulating tumor cells and cell-free DNA from tumors has led to the use of these alterations as potential biomarkers in early detection and diagnosis, as well as prognosis, in breast cancer. Panels of tumor-specific methylated genes in cell-free DNA with potential value for early detection of breast cancer have been described by Kloten et al34Kloten V. Becker B. Winner K. Schrauder M.G. Fasching P.A. Anzeneder T. Veeck J. Hartmann A. Knuchel R. Dahl E. Promoter hypermethylation of the tumor-suppressor genes ITIH5, DKK3, and RASSF1A as novel biomarkers for blood-based breast cancer screening.Breast Cancer Res. 2013; 15: R4Crossref PubMed Scopus (0) Google Scholar (ITIH5, DKK3, and RASSF1A) and Shan et al35Shan M. Yin H. Li J. Li X. Wang D. Su Y. Niu M. Zhong Z. Wang J. Zhang X. Kang W. Pang D. Detection of aberrant methylation of a six-gene panel in serum DNA for diagnosis of breast cancer.Oncotarget. 2016; 7: 18485-18494Crossref PubMed Scopus (1) Google Scholar (SFN, CDKN2A, MLH1, HOXD13, PCDHGB7, and RASSF1A). RASSF1A and PITX2 hypermethylation has been associated with poor prognosis and pathogenesis in the early stages of breast cancer.36Gobel G. Auer D. Gaugg I. Schneitter A. Lesche R. Muller-Holzner E. Marth C. Daxenbichler G. Prognostic significance of methylated RASSF1A and PITX2 genes in blood- and bone marrow plasma of breast cancer patients.Breast Cancer Res Treat. 2011; 130: 109-117Crossref PubMed Scopus (36) Google Scholar, 37Jezkova E. Kajo K. Zubor P. Grendar M. Malicherova B. Mendelova A. Dokus K. Lasabova Z. Plank L. Danko J. 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Muller V. Milde-Langosch K. Nahrig J. Foekens J. Maier S. Schmitt M. Lesche R. Multicenter study using paraffin-embedded tumor tissue testing PITX2 DNA methylation as a marker for outcome prediction in tamoxifen-treated, node-negative breast cancer patients.J Clin Oncol. 2008; 26: 5036-5042Crossref PubMed Scopus (68) Google Scholar Epigenetic regulation is also a well-recognized mechanism controlling epithelial mesenchymal transition in breast cancer progression. Thus, hypermethylation of CDH1 is a common event in breast tumors and has been associated with the triple-negative phenotype.40Roll J.D. Rivenbark A.G. Sandhu R. Parker J.S. Jones W.D. Carey L.A. Livasy C.A. Coleman W.B. Dysregulation of the epigenome in triple-negative breast cancers: basal-like and claudin-low breast cancers express aberrant DNA hypermethylation.Exp Mol Pathol. 2013; 95: 276-287Crossref PubMed Scopus (0) Google Scholar, 41Naghitorabi M. Mohammadi-Asl J. Sadeghi H.M. Rabbani M. Jafarian-Dehkordi A. Javanmard S.H. Quantitation of CDH1 promoter methylation in formalin-fixed paraffin-embedded tissues of breast cancer patients using differential high resolution melting analysis.Adv Biomed Res. 2016; 5: 91Crossref PubMed Google Scholar CDH1 hypermethylation is a poor-prognosis factor and has been postulated as a novel therapeutic target for the treatment of ER-negative or HER2-negative breast cancer with aggressive tumor biology.42Liu J. Sun X. Qin S. Wang H. Du N. Li Y. Pang Y. Wang C. Xu C. Ren H. CDH1 promoter methylation correlates with decreased gene expression and poor prognosis in patients with breast cancer.Oncol Lett. 2016; 11: 2635-2643Crossref PubMed Scopus (6) Google Scholar, 43Huang R. Ding P. Yang F. Clinicopathological significance and potential drug target of CDH1 in breast cancer: a meta-analysis and literature review.Drug Des Devel Ther. 2015; 9: 5277-5285PubMed Google Scholar Furthermore, we have reported aberrant methylation of other epithelial mesenchymal transition–related genes in breast tumors, including ITGA5, TINAGL1, FKBP10, and ESYT3, with hypermethylation of the latter being a poor-prognosis factor in breast cancer.44Carmona F.J. Davalos V. Vidal E. Gomez A. Heyn H. Hashimoto Y. Vizoso M. Martinez-Cardus A. Sayols S. Ferreira H.J. Sanchez-Mut J.V. Moran S. Margeli M. Castella E. Berdasco M. Stefansson O.A. Eyfjord J.E. Gonzalez-Suarez E. Dopazo J. Orozco M. Gut I.G. Esteller M. A comprehensive DNA methylation profile of epithelial-to-mesenchymal transition.Cancer Res. 2014; 74: 5608-5619Crossref PubMed Scopus (0) Google Scholar Some remarkable epigenetically regulated genes that have been associated with breast carcinogenesis are listed in Table 1.Table 1Epigenetic Regulated Genes in Breast Cancer∗In all of the listed genes, aberrant 5'-C-phosphate-G-3' (CpG) hypermethylation is the epigenetic event occurring in breast cancer.GeneBiological and clinical relevanceReferencesESR1Carcinogenesis, associated with ER− breast tumors and PR status; poor prognosis and poor response to antiestrogen agents13Widschwendter M. Siegmund K.D. Muller H.M. Fiegl H. Marth C. Muller-Holzner E. Jones P.A. Laird P.W. Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen.Cancer Res. 2004; 64: 3807-3813Crossref PubMed Scopus (0) Google Scholar, 14Gaudet M.M. Campan M. Figueroa J.D. Yang X.R. Lissowska J. Peplonska B. Brinton L.A. Rimm D.L. Laird P.W. Garcia-Closas M. Sherman M.E. DNA hypermethylation of ESR1
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