Epigenetic information and estrogen receptor alpha expression in breast cancer.

In industrialized countries, breast cancer is the most common tumor in women. The tumor expression of estrogen receptors (ERs) is a very important marker for prognosis and a marker that is predictive of response to endocrine therapy. The loss of ER expression portends a poor prognosis and, in a significant fraction of breast cancers, this repression is a result of the hypermethylation of CpG islands within the ER-alpha promoter. Hypermethylation is one of the best known epigenetic events in mammalian cells. Over the last few years, many studies have found that other epigenetic events, such as deacetylation and methylation of histones, are involved in the complex mechanism that regulates promoter transcription. The exact interplay of these factors in transcriptional repression activity is not yet well understood. Inhibitors of some of these are currently being studied as new drugs able to restore ER-alpha protein expression in ER-alpha-negative breast cancer cells and to promote apoptosis and differentiation. Demethylating agents and histone deacetylase (HDAC) inhibitors are candidates for becoming potent new drugs in cancer therapy. This paper reviews the current understanding of the role of epigenetic information in the development of cancer and its significance in breast cancer as predictive markers of ER status and as new targets of anticancer therapy.

[1]  M. Fraga,et al.  Human DNA Methyltransferase 1 Is Required for Maintenance of the Histone H3 Modification Pattern* , 2004, Journal of Biological Chemistry.

[2]  P. Munster,et al.  Sequence‐specific potentiation of topoisomerase II inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acid , 2004, Journal of cellular biochemistry.

[3]  P. Marks.  The Mechanism of the Anti-Tumor Activity of the Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid (SAHA) , 2004, Cell cycle.

[4]  S. Angeloni,et al.  Regulation of estrogen receptor-alpha expression in MCF-7 cells by taxol. , 2004, The Journal of endocrinology.

[5]  M. Beckmann,et al.  Insights into the molecular biology of the estrogen receptor define novel therapeutic targets for breast cancer. , 2004, European journal of endocrinology.

[6]  S. Angeloni,et al.  Regulation of estrogen receptor- expression by the tumor suppressor gene p53 in MCF-7 cells , 2004 .

[7]  J. McNally,et al.  Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription. , 2004, Nucleic acids research.

[8]  G. Felsenfeld,et al.  Silencing of transgene transcription precedes methylation of promoter DNA and histone H3 lysine 9 , 2004, The EMBO journal.

[9]  Esteban Ballestar,et al.  Methyl‐CpG binding proteins identify novel sites of epigenetic inactivation in human cancer , 2003, The EMBO journal.

[10]  A. Shaaban,et al.  Declining Estrogen Receptor-&bgr; Expression Defines Malignant Progression of Human Breast Neoplasia , 2003, The American journal of surgical pathology.

[11]  H. Kawai,et al.  Overexpression of histone deacetylase HDAC1 modulates breast cancer progression by negative regulation of estrogen receptor α , 2003, International journal of cancer.

[12]  Myles Brown,et al.  Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy , 2003, Breast Cancer Research.

[13]  E. Knudsen,et al.  Histone Deacetylation of RB-Responsive Promoters: Requisite for Specific Gene Repression but Dispensable for Cell Cycle Inhibition , 2003, Molecular and Cellular Biology.

[14]  Daniel Delorme,et al.  Novel hydroxamate and anilide derivatives as potent histone deacetylase inhibitors: synthesis and antiproliferative evaluation. , 2003, Current medicinal chemistry.

[15]  Dipali Sharma,et al.  A Novel Histone Deacetylase Inhibitor, Scriptaid, Enhances Expression of Functional Estrogen Receptor α (ER) in ER negative human breast cancer cells in combination with 5-aza 2′-deoxycytidine , 2003, Breast Cancer Research and Treatment.

[16]  M. Paz,et al.  Genetic unmasking of epigenetically silenced tumor suppressor genes in colon cancer cells deficient in DNA methyltransferases. , 2003, Human molecular genetics.

[17]  M. Nakao,et al.  Methyl-CpG Binding Domain 1 (MBD1) Interacts with the Suv39h1-HP1 Heterochromatic Complex for DNA Methylation-based Transcriptional Repression* , 2003, Journal of Biological Chemistry.

[18]  Caterina Cinti,et al.  pRb2/p130-E2F4/5-HDAC1-SUV39H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 multimolecular complexes mediate the transcription of estrogen receptor-α in breast cancer , 2003, Oncogene.

[19]  J. Herman,et al.  Specific Inhibition of DNMT1 by Antisense Oligonucleotides Induces Re-expression of Estrogen Receptor a (ER) in ER-negative Human Breast Cancer Cell Lines , 2003, Cancer biology & therapy.

[20]  G. Otterson,et al.  The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. , 2003, Current medicinal chemistry. Anti-cancer agents.

[21]  J. González-Ros,et al.  Susceptibility of multidrug resistance tumor cells to apoptosis induction by histone deacetylase inhibitors , 2003, International journal of cancer.

[22]  T. Kouzarides,et al.  The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. , 2003, Nucleic acids research.

[23]  S. Haggarty,et al.  Chemical genetic modifier screens: small molecule trichostatin suppressors as probes of intracellular histone and tubulin acetylation. , 2003, Chemistry & biology.

[24]  H. Iwase.  Molecular action of the estrogen receptor and hormone dependency in breast cancer , 2003, Breast cancer.

[25]  Tony Kouzarides,et al.  The Methyl-CpG-binding Protein MeCP2 Links DNA Methylation to Histone Methylation* , 2003, The Journal of Biological Chemistry.

[26]  Daniel Delorme,et al.  Development of potential antitumor agents. Synthesis and biological evaluation of a new set of sulfonamide derivatives as histone deacetylase inhibitors. , 2003, Journal of medicinal chemistry.

[27]  P. Driggers,et al.  Estrogen action and cytoplasmic signaling pathways. Part II: the role of growth factors and phosphorylation in estrogen signaling , 2002, Trends in Endocrinology & Metabolism.

[28]  M. Esteller.  CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future , 2002, Oncogene.

[29]  Donald P. McDonnell,et al.  Connections and Regulation of the Human Estrogen Receptor , 2002, Science.

[30]  Bert Vogelstein,et al.  DNMT1 and DNMT3b cooperate to silence genes in human cancer cells , 2002, Nature.

[31]  J. P. Jackson,et al.  Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase , 2002, Nature.

[32]  T. Kouzarides.  Histone methylation in transcriptional control. , 2002, Current opinion in genetics & development.

[33]  E. Nicolas,et al.  Functional and physical interaction between the histone methyl transferase Suv39H1 and histone deacetylases. , 2002, Nucleic acids research.

[34]  N. Rosen,et al.  The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. , 2001, Cancer research.

[35]  E. Selker,et al.  A histone H3 methyltransferase controls DNA methylation in Neurospora crassa , 2001, Nature.

[36]  J. Herman,et al.  Synergistic activation of functional estrogen receptor (ER)-α by DNA methyltransferase and histone deacetylase inhibition in human ER-α-negative breast cancer cells , 2001 .

[37]  E. Nicolas,et al.  Transcriptional Repression by the Retinoblastoma Protein through the Recruitment of a Histone Methyltransferase , 2001, Molecular and Cellular Biology.

[38]  Andrew J. Bannister,et al.  Rb targets histone H3 methylation and HP1 to promoters , 2001, Nature.

[39]  Keith D Robertson,et al.  DNA methylation, methyltransferases, and cancer , 2001, Oncogene.

[40]  T. Kouzarides,et al.  Dnmt3a binds deacetylases and is recruited by a sequence‐specific repressor to silence transcription , 2001, The EMBO journal.

[41]  E. Selker,et al.  Emerging connections between DNA methylation and histone acetylation , 2001, Cellular and Molecular Life Sciences CMLS.

[42]  J. Herman,et al.  A gene hypermethylation profile of human cancer. , 2001, Cancer research.

[43]  Andrew J. Bannister,et al.  Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain , 2001, Nature.

[44]  Karl Mechtler,et al.  Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins , 2001, Nature.

[45]  D. Medina,et al.  Mechanisms of suberoylanilide hydroxamic acid inhibition of mammary cell growth , 2000, Breast Cancer Research.

[46]  J. Herman,et al.  Transcriptional activation of estrogen receptor alpha in human breast cancer cells by histone deacetylase inhibition. , 2000, Cancer research.

[47]  C. Ponting,et al.  Regulation of chromatin structure by site-specific histone H3 methyltransferases , 2000, Nature.

[48]  Peter L. Jones,et al.  DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters , 2000, Nature Genetics.

[49]  S. Baylin,et al.  DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci , 2000, Nature Genetics.

[50]  M. Caligiuri,et al.  Aberrant CpG-island methylation has non-random and tumour-type–specific patterns , 2000, Nature Genetics.

[51]  J. Herman,et al.  In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[52]  E Gabrielson,et al.  Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[53]  L. Magnaghi-Jaulin,et al.  The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[54]  A. Ferguson,et al.  Demethylation of the progesterone receptor CpG island is not required for progesterone receptor gene expression , 1998, Oncogene.

[55]  S. Weitzman,et al.  Mapping of ER gene CpG island methylation-specific polymerase chain reaction. , 1998, Cancer research.

[56]  J. Strouboulis,et al.  Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription , 1998, Nature Genetics.

[57]  Colin A. Johnson,et al.  Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex , 1998, Nature.

[58]  Carolyn L. Smith,et al.  Cross-talk between peptide growth factor and estrogen receptor signaling pathways. , 1998, Biology of reproduction.

[59]  Tony Kouzarides,et al.  Retinoblastoma protein recruits histone deacetylase to repress transcription , 1998, Nature.

[60]  S. Baylin,et al.  Role of Estrogen Receptor Gene Demethylation and DNA Methyltransferase·DNA Adduct Formation in 5-Aza-2′deoxycytidine-induced Cytotoxicity In Human Breast Cancer Cells* , 1997, The Journal of Biological Chemistry.

[61]  A. Bird,et al.  MeCP2 Is a Transcriptional Repressor with Abundant Binding Sites in Genomic Chromatin , 1997, Cell.

[62]  R. Weigel,et al.  Transcriptional control of estrogen receptor in estrogen receptor-negative breast carcinoma. , 1993, Cancer research.

[63]  A. Bird,et al.  Purification, sequence, and cellular localization of a novel chromosomal protein that binds to Methylated DNA , 1992, Cell.

[64]  A. Bird,et al.  Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs , 1989, Cell.

[65]  A. Bird.  CpG-rich islands and the function of DNA methylation , 1986, Nature.

[66]  L. Arrighi,et al.  [Treatment of breast cancer]. , 1971, Prensa medica argentina.

[67]  S. Nass,et al.  The Loss of Estrogen and Progesterone Receptor Gene Expression in Human Breast Cancer , 2004, Journal of Mammary Gland Biology and Neoplasia.

[68]  P. Marks,et al.  Histone deacetylase inhibitors: development as cancer therapy. , 2004, Novartis Foundation symposium.

[69]  M. Robert,et al.  DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells , 2003, Nature Genetics.

[70]  A. Bird.  DNA methylation patterns and epigenetic memory. , 2002, Genes & development.

[71]  J. Herman,et al.  Synergistic activation of functional estrogen receptor (ER)-alpha by DNA methyltransferase and histone deacetylase inhibition in human ER-alpha-negative breast cancer cells. , 2001, Cancer research.

[72]  A. Wolffe,et al.  DNA methylation and histone deacetylation in the control of gene expression: basic biochemistry to human development and disease. , 2000, Gene expression.

[73]  S. Weitzman,et al.  Mapping of ER gene CpG island methylation-specific polymerase chain reaction. , 1998, Cancer research.