Journal of Mammary Gland Biology and Neoplasia

, Volume 6, Issue 2, pp 183–192

Role of DNA Methylation and Histone Acetylation in Steroid Receptor Expression in Breast Cancer

Article

Abstract

DNA methylation is an epigenetic modification that is associated with transcriptional silencing of gene expression in mammalian cells. Hypermethylation of the promoter CpG islands contributes to the loss of gene function of several tumor related genes, including estrogen receptor α (ER) and progesterone receptor (PR). Gene expression patterns are also heavily influenced by changes in chromatin structure during transcription. Indeed both the predominant mammalian DNA methyltransferase (DNMT1), and the histone deacetylases (HDACs) play crucial roles in maintaining transcriptionally repressive chromatin by forming suppressive complexes at replication foci. These new findings suggest that epigenetic changes might play a crucial role in gene inactivation in breast cancer. Further, inhibition of DNA methylation and histone deacetylation might be a therapeutic strategy in breast cancer, especially for those cancers with ER and PR negative phenotypes.

Breast cancer DNA methylation histone acetylation steroid receptor 

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REFERENCES

  1. 1.
    M. Ehrlich, M. A. Gama-Sosa, L. H. Huang, R. M. Midgett, K. C. Kuo, R. A. McCune, and C. Gehrke (1982). Amount and distribution of 5-methylcytosine in human DNA from different types of cells. Nucleic Acids Res. 10:2709–2721.Google Scholar
  2. 2.
    A. P. Bird (1986). CpG-rich islands and the function of DNA methylation. Nature 321:209–213.Google Scholar
  3. 3.
    S. U. Kass, D. Pruss, and A. P. Wolffe (1997). How does DNA methylation repress transcription? Trends Genet. 13:444–449.Google Scholar
  4. 4.
    M. S. Bartolomei and S. M. Tilghman (1997). Genomic imprinting in mammals. Ann. Rev. Genet. 31:493–525.Google Scholar
  5. 5.
    R. Jaenisch, C. Beard, J. Lee, Y. Marahrens, and B. Panning (1998). Mammalian X chromosome inactivation. Novartis Foundation Symp. 214:200–209.Google Scholar
  6. 6.
    S. B. Baylin and J. G. Herman (2000). DNA hypermethylation in tumorigenesis. Trends Genet. 16:168–174.Google Scholar
  7. 7.
    M. S. Tucker and T. H. Bestor (1997). Formation of methylation patterns in mammalian genome. Mutation Res. 386:119–130.Google Scholar
  8. 8.
    E. Li., T. H. Bestor, and R. Jaenisch (1992). Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69:615–926.Google Scholar
  9. 9.
    Y. Liu, E. J. Oakeley, L. Sun, and J. P. Jost (1998). Multiple domains are involved in the targeting of the mouse DNA methyltransferase in the DNA replication foci. Nucleic Acids Res. 26:1038–1045.Google Scholar
  10. 10.
    I. Rhee, K W. Jair, R. W. C. Yen, C. Lengauer, J. G. Herman, K. W. Kinzler, B. Vogelstein, S. B. Baylin and K. E. Schuebel (2000). CpG methylation is maintained in human cancer cells lacking DNMT1. Nature 404:1003–1007.Google Scholar
  11. 11.
    J. A. Yoder and T. H. Bestor (1998). A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast. Humar Mol. Genet. 7:279–284.Google Scholar
  12. 12.
    M. Okano, S. Xie, and E. Li (1998). Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells. Nucleic Acids Res. 26:2536–2540.Google Scholar
  13. 13.
    V. Wyngaert, J. Sprengel, S. U. Kass, and W. H. Luyten (1998). Cloning and analysis of a novel human putative DNA methyltransferase. FEBS Lett. 426:283–289.Google Scholar
  14. 14.
    M. Okano, S. Xie, and E. Li (1998). Cloning and characterization of a family of novel mammalian DNA(cytosine-5) methyltransferases. Nature Genet. 19:219–220.Google Scholar
  15. 15.
    S. Xie, Z. Wang, M. Okano, M. Nogami, Y. Li, W. W. He, K. Okumura, and E. Li (1999). Cloning, expression and chromosome locations of the human DNMT3 gene family. Gene 236:87–95.Google Scholar
  16. 16.
    S. E. Goelz, B. Vogelstein, S. R. Hamilton, and A. P. Feinberg (1985). Hypomethylation of DNA from benign and malignant human colon neoplasms. Science 228:187–190.Google Scholar
  17. 17.
    L. Momparler and V. Bovenzi (2000). DNA methylation and cancer. J. Cell. Physiol. 183:145–154.Google Scholar
  18. 18.
    S. A. Belinsky, K. J. Nikula, W. A. Palmisano, R. Michels, G. Saccomanno, E. Gabrielson, S. B. Baylin, and J. G. Herman (1998). Aberrant methylation of p16INK4a is an early event in lung cancer and a potential biomarker for early diagnosis. Proc. Natl. Acad. Sci. U.S.A. 95:11891–11896.Google Scholar
  19. 19.
    D. J. Wong, S. A. Foster, D. A. Galloway, and B. J. Reid (1999). Progressive region-specific de novo methylation of the p16CpG island in primary human mammary epithelial cell strains during escape from M(0) growth arrest. Mol. Cell. Biol. 19:5642–5651.Google Scholar
  20. 20.
    G. J. Nuovo, T. W. Plaia, S. A. Belinsky, S. B. Baylin, and J.G. Herman (1999). In situ detection of the hypermethylationinduced inactivation of the p16 gene as an early event in oncogenesis. Proc. Natl. Acad. Sci. U.S.A. 96:12754–12759.Google Scholar
  21. 21.
    T. Kiyono, S. A. Foster, J. I. Koop, J. K. McDougall, D. A. Galloway, and A. J. Klingelhutz (1998). Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature 396:84–88.Google Scholar
  22. 22.
    J. G. Herman, A. Umar, K. Polyak, J. R. Graff, N. Ahuja, J. P. Issa, S. Markowitz, J. K. Wilson, S. R. Hamilton, K.W. Kinzler, M. F. Kane, R. D. Kolodner, B. Vogelstein, T. A. Kunkel, and S. B. Baylin (1998). Incidence and functional consequences of hMLH1 promoter hpermethylation in colorectal carcinoma. Proc. Natl. Acad. Sci. U.S.A. 95:6870–6875.Google Scholar
  23. 23.
    M. Esteller, L. Catasus, X. Matias-Guiux, G. L. Mutter, J. Prat, S. B. Baylin and J. G. Herman (1999). HMLH1 promoter hypermethylation is an early event in human endometrial tumorigenesis. Amer. J. Pathol. 155:1767–1772.Google Scholar
  24. 24.
    W. H. Lee, R. A. Morton, J. I. Epstein, J. D. Brooks, P. A. Campbell, G. S. Bova, W. S. Hsieh, W. B. Issacs, and W. G. Nelson (1994). Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc. Natl. Acad. Sci. U.S.A. 91:11733–11737.Google Scholar
  25. 25.
    M. Esteller, P. G. Corn, J. M. Urena, E. Gabrielson, S. B. Baylin, and J. G. Herman (1998). Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human neoplasia. Cancer Res. 58:4515–4518.Google Scholar
  26. 26.
    M. Grunstein (1997). Histone acetylation in chromatin structure and transcription. Nature 389:349–352.Google Scholar
  27. 27.
    C. A. Mizzen and C.D. Allis (1998). Linking histone acetylation to transcriptional regulation. Cell Mol. Life Sci. 54:6–20.Google Scholar
  28. 28.
    C. A. Hassig, J. K. Tong, T. C. Fleischer, T. Owa, P. G. Grable, D. E. Ayer, and S. L. Schreiber (1998). A role for histone deacetylase activity in HDAC1-mediated transcriptional repression. Proc. Natl. Acad. Sci. U.S.A. 95:3519–3524.Google Scholar
  29. 29.
    U. H. Weidle and A. Grossmann (2000). Inhibition of histone deacetylases: Anew strategy to target epigenetic modifications for anticancer treatment. Anticancer Res. 20:1471–1486.Google Scholar
  30. 30.
    T. Taki, M. Sako, M. Tsuchida, and Y. Hayashi (1997). The t(11;16) (q23;p13) translocation in myelodysplastic syndrome fuses the MLL gene to the CBP gene. Blood 89:3945–3950.Google Scholar
  31. 31.
    O. M. Sobulo, J. Borrow, R. Tomek, S. Reshmi, A. Harden, B. Schlegelberger, D. Housman, N. A. Doggett, J. D. Rowley, and N. J. Zeleznik-Le (1997). MLLis fused to CBP, a histone acetyltranferase, in therapy-related acute myeloid leukemia with a t(11;16) (q23;p13.3). Proc. Natl. Acad. Sci. U.S.A. 94:8732–8737.Google Scholar
  32. 32.
    R. I. Yarden and L. C. Brody (1999). BRCA1 interacts with components of the histone deacetylase complex. Proc. Natl. Acad. Sci. U.S.A. 96:4983–4988.Google Scholar
  33. 33.
    I. Irminger-Finger, B. D. Siegel, and W. C. Leung (1999). The functions of breast cancer susceptibility gene 1 (BRCA1) and its associated proteins. Biol. Chem. 380:117–128.Google Scholar
  34. 34.
    H. Siddique, J. P. Zou, V. N. Rao, and E. S. P. Reddy (1998). The BRCA2 is a histone acetyltransferase. Oncogene 16:2283–2285.Google Scholar
  35. 35.
    L.M. Mielnicki, H. L. Asch, and B.B. Asch(2001). Genes, Chromatin, and breast cancer: An epigenetic tale. J. Mam. Gland Biol. Neoplasia, 6(2).Google Scholar
  36. 36.
    T. H. Bestor (1998). Methylation meets acetylation. Nature 393:311–312.Google Scholar
  37. 37.
    S. Eden, T. Hashimshony, I. Keshet, H. Cedar, and A.W. Thorne (1998). DNA methylation models histone acetylation. Nature 394:842.Google Scholar
  38. 38.
    M. R. Rountree, K. E. Bachman, and S. B. Baylin (2000). DNMT1 binds HDAC2 and a new co-represor, DNMAP1, to form a complex at replication foci. Nat. Genet. 25:269–277.Google Scholar
  39. 39.
    K. D. Robertson, S. Ait-Si-Ali, T. Yokochi, P. A. Wade, P. L. Jones, and A. P. Wolffe (2000). DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2Fresponsive promoters. Nat. Genet. 25:338–342.Google Scholar
  40. 40.
    R.G. Lapidus, S. J. Nass, and N. E. Davidson (1998). The loss of estrogen and progesterone receptor gene expression in human breast cancer. J. Mam. Gland Biol. Neoplasia 3:85–94.Google Scholar
  41. 41.
    D. L. Ricketts, G. Turnbull, R. Ryall, N. S. B. Baskshi, N. S. B. Raswon, J-C. Gazet, C. Nolan, and R. C. Coombes (1991). Estrogen and progesterone receptor in the normal female breast. Cancer Res. 51:1817–1822.Google Scholar
  42. 42.
    O. W. Peterson, P. E. Hoyer, and B. Van Deur (1987). Frequency and distribution of estrogen positive cells in normal, non-lactating human breast tissue. Cancer Res. 47:5748–5751.Google Scholar
  43. 43.
    W. L. McGuire (1978). Hormone receptors: Their role in predicting prognosis and response to endocrine therapy. Seminar Oncol. 5:428–433.Google Scholar
  44. 44.
    T. Kuukasjarvi, J. Kononen, K. Helin, K. Holli, and J. Isola (1996). Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J. Clin. Oncol. 14:25284–25289.Google Scholar
  45. 45.
    G. L. Greene, P. Hilna, M. Waterfield, A. Baker, Y. Hort, and J. Shine (1986). Sequence and expression of human estrogen receptor complementary DNA. Science 231:1150–1154.Google Scholar
  46. 46.
    S. Green, P. Walter, V. Kumar, A. Krust, P-M. Bornet, P. Argos, and P. Chambon (1986). Human oestrogen receptor cDNA: Sequence, expression and homology to v-erb-A. Nature 320:134–139.Google Scholar
  47. 47.
    M. Ponglikitmonkol, S. Green, and P. Chambon (1988). Genomic organization of the human oestrogen receptor gene. EMBO J. 7:3385–3388.Google Scholar
  48. 48.
    R. Piva, R. Gambari, F. Zorzato, L. Kumar, and L. del Senno (1992). Analysis of upstream sequences of the human estrogen receptor gene. Biochem. Biophys. Res. Commun. 183:996–1002.Google Scholar
  49. 49.
    R. J. Weigel and E. C. de Coninck (1993). Transcriptional control of estrogen receptor in estrogen receptor-negative breast carcinoma. Cancer Res. 53:3472–3474.Google Scholar
  50. 50.
    Y. L. Ottaviano, J-P. Issa, F. F. Parl, H. S. Smith, S. B. Baylin, and N. E. Davidson (1994). Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res. 54:2552–2555.Google Scholar
  51. 51.
    S. J. Nass, A. T. Ferguson, D. El-Ashry, W. G. Nelson, and N. E. Davidson (1999). Expression of DNA methyltransferase (DNMT) and the cell cycle in human breast cancer cells. Oncogene 18:7453–7461.Google Scholar
  52. 52.
    R. G. Lapidus, A. T. Ferguson, Y. L. Ottaviano, F. F. Parl, S. B. Baylin, J-P. J. Issa, and N. E. Davidson (1996). Methylation of estrogen and progesterone receptor gene 50 CpG islands correlates with lack of estrogen and progesterone receptor gene expression in breast tumors. Clin. Cancer Res. 2:805–810.Google Scholar
  53. 53.
    R.G. Lapidus, S. J. Nass, K.A. Butash, F.F. Parl, S. A. Weitzman, J. G. Graff, J. G. Herman, and N. E. Davidson (1998). Mapping of ER gene CpG island methylation by methylation-specific polymerase chain reaction. Cancer Res. 58:2515–2519.Google Scholar
  54. 54.
    H. Iwase, Y. Omoto, H. Iwata, T. Toyama, Y. Hara, Y. Ando, Y. Ito, Y. Fujii, and S. Kobayashi (1999). DNAmethylation analysis at distal and proximal promoter regions of the oestrogen receptor gene in breast cancers. Brit. J. Cancer 80:1982–1986.Google Scholar
  55. 55.
    A. T. Ferguson, R.G. Lapidus, S. B. Baylin, and N. E. Davidson (1995). Demethylation of the estrogen receptor gene in estrogen receptor-negative breast cancer cells can reactivate estrogen receptor gene expression. Cancer Res. 55:2279–2283.Google Scholar
  56. 56.
    L. D. Read, C. E. Snider, J. S. Miller, G. L. Greene, and B. S. Katzenellenbogen. (1988). Ligand-modulated regulation of progesterone receptor messenger ribonucleic acid and protein in human breast cancer cell lines. Mol. Endocrinol. 2:263–271.Google Scholar
  57. 57.
    A. T. Ferguson, R. G. Lapidus and N. E. Davidson (1998). Demethylation of the progesterone receptor CpG island is not required for progesterone receptor gene expression. Oncogene 17:577–583.Google Scholar
  58. 58.
    E. E. Cameron, K. E. Bachman, S. Myohanen, J. G. Herman, and S. B. Baylin (1999). Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat. Genet. 21:103.Google Scholar
  59. 59.
    X. Nan, H. H. Ng, C. A. Johnson, C. D. Laherty, B. M. Turner, T. N. Eisenman, and A. Bird (1998). Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386–389.Google Scholar
  60. 60.
    P. L. Jones, G. J. Veenstra, P. A. Wade, D. Vermaak, S. U. Kass, N. Landsberger, J. Strouboulis, and A. P. Woffe (1998). Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat. Genet. 19:187–189.Google Scholar
  61. 61.
    R. J. Lin, L. Nagy, S. Inoue, W. Shao, W. H. Jr. Miller, and R. M. Evans (1998). Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391:811–814.Google Scholar
  62. 62.
    F. Grignani, S. DeMatteis, C. Nervi, L. Tomassoni, V. Gelmetti, M. Cioce, M. Fanelli, M. Ruthardt, F. F. Ferrara, I. Zamir, C. Seiser, F. Grignani, M. A. Lazar, S. Minucci, and P. G. Pellicci (1998). Fusion proteins of the retinoic acid receptor-? recruit histone deacetylase in promyelocytic leukaemia. Nature 391:815–818.Google Scholar
  63. 63.
    R. P. Warrell, Jr., L. Z. He, V. Richon, E. Calleja, and P. P. Pandolfi (1998). Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J. Natl. Cancer Inst. 90:1621–1625.Google Scholar
  64. 64.
    X. Yang, A. T. Ferguson, S. J. Nass, D. L. Philips, K. A. Butash, S.M. Wang, J.G. Herman, and N. E. Davidson (2000). Transcriptional activation of estrogen receptor ? in human breast cancer cells by histone deacetylase inhibition. Cancer Res. 60:6890–6894.Google Scholar
  65. 65.
    S. Charache, G. Dover, K. Smith, C. C. Talbot, Jr., M. Moyer, and S. Boyer (1983). Treatment of sickle cell anemia with 5-azacytidine results in increased fetal hemoglobin production and is associated with nonrandom hypomethylation around the ?-?-? globin gene complex. Proc. Natl. Acad. Sci. U.S.A. 80:4842–4846.Google Scholar
  66. 66.
    T. J. Ley, J. DeSimone, N. P. Anagnou, G. H. Keller, R. K. Humphries, P. H. Turner, N. S. Young, P. Keller, and A. W. Nienhuis (1982). 5-azacytidine selectively increases ?-globin synthesis in a patient with ?-thalassemia. N. Engl. J. Med. 307:1469–1475.Google Scholar
  67. 67.
    G. J. Dover, S. Charache, S. H. Boyer, G. Vogelsang, and M. Moyer (1985). 5-azacytidine increased HbF production and reduces anemia in sickle cell disease. Dose-response analysis of subcutaneous and oral dosing regimens. Blood 66:527–532.Google Scholar
  68. 68.
    A. R. MacLeod and M. Szyf (1995). Expression of antisense to DNA methyltransferase mRNA induces DNA demethylation and inhibits tumorigenesis. J. Biol. Chem. 270:8037–8043.Google Scholar
  69. 69.
    S. Ramchandani, A. R. MacLeod, M. Pinard, E. von Hofe, and M. Szyf (1997). Inhibition of tumorigenesis by a cytosine-DNA, methyltransferase, antisense oligonucleotide. Proc. Natl. Acad. Sci. U.S.A. 94:684–690.Google Scholar
  70. 70.
    B. G. Heerdt, M. A. Houston, G. M. Anthony, and L. H. Augenlicht (1999). Initiation of growth arrest and apoptosis of MCF-7 mammary carcinoma cells by tributyrin, a triglyceride analogue of the short-chain fatty acid butyrate, is associated with mitochondrial activity. Cancer Res. 59:1584–1591.Google Scholar
  71. 71.
    M. A. Carducci, J. B. Nelson, K. M. Chan-Tack, S. R. Ayyagari, W. H. Sweatt, P. A. Campbell, W. G. Nelson, and J. W. Simons (1996). Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate. Clin. Cancer Res. 2:379–387.Google Scholar
  72. 72.
    A. F. Collins, H.A. Pearson, P. Giardina, K. T. McDonagh, S.W. Brusilow, and G. J. Dover (1995). Oral sodium phenylbutyrate therapy in homozygous ?-thalassemia: A clinical trial. Blood 85:43–49.Google Scholar
  73. 73.
    L. A. McPherson and R. J. Weigel (1999). AP2? and AP2?: A comparison of binding site specificity and trans-activation of the estrogen receptor promoter and single site promoter constructs. Nucleic Acids Res. 27:4040–4049.Google Scholar

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  1. 1.Johns Hopkins Oncology CenterBaltimore

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