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Article
Nature Genetics  7, 536 - 540 (1994)
doi:10.1038/ng0894-536

Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon

Jean-Pierre J. Issa1, 4, Yvonne L. Ottaviano1, Paul Celano1, Stanley R. Hamilton2, Nancy E. Davidson1 & Stephen B. Baylin3

  1The Oncology Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21205, USA

  2Department of Pathology, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21205, USA

  3Department of Medicine, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21205, USA

  4Correspondence should be addressed to J.−P.J.I.

We report that CpG island methylation, an epigenetic modification of DNA known to correlate closely with silencing of gene transcription, appears in the oestrogen receptor (ER) gene in a subpopulation of cells which increases as a direct function of age in human colonic mucosa. This same methylation change characterizes virtually all cells in all 45 colorectal tumours examined, including the earliest stages of tumour formation. ER gene expression is diminished or absent in colorectal tumours, and introduction of an exogenous ER gene in cultured colon carcinoma cells resulted in marked growth suppression. Our data suggest that methylation associated inactivation of the ER gene in ageing colorectal mucosa could be one of the earliest events that predispose to sporadic colorectal tumorigenesis.

REFERENCES
  1. Bird, A.P. CpG-rich islands and the function of DNA methylation. Nature 321, 209−213 (1986). | PubMed  | ISI | ChemPort |
  2. Migeon, B.R. Insights into X chromosome inactivation from studies of species variation, DNA methylation and replication, and vice versa. Genet. Res. 56, 91−98 (1990). | PubMed  | ISI | ChemPort |
  3. Singer-Sam, J. & Riggs, A.D. X chromosome inactivation and DNA methylation. EXS 64, 358−384 (1993). | PubMed  | ChemPort |
  4. Ferguson-Smith, A.C., Sasaki, H., Cattanach, B.M. & Surani, M.A. Parental-origin-specific epigenetic modification of the mouse H19 gene. Nature 362, 751−755 (1993). | Article | PubMed  | ChemPort |
  5. Bartolomei, M.S., Webber, A.L., Brunkow, M.E. & Tilghman, S.M. Epigenetic mechanisms underlying the imprinting of the mouse H19 gene. Genes Devel. 7, 1663−1673 (1993). | PubMed  | ISI | ChemPort |
  6. Li, E., Beard, C. & Jaenisch, R. Role for DNA methylation in genomic imprinting. Nature 366, 362−365 (1993). | Article | PubMed  | ISI | ChemPort |
  7. Hayashizaki, Y. et al. Identification of an imprinted U2af binding protein related sequence on mouse chromosome 11 using the RLGS method. Nature Genet. 6, 33−40 (1994). | Article | PubMed  | ISI | ChemPort |
  8. Stoger, R. et al. Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Cell 73, 61−71 (1993). | Article | PubMed  | ISI | ChemPort |
  9. de Bustros, A. et al. The short arm of chromosome 11 is a "hot spot" for hypermethylation in human neoplasia. Proc. natn. Acad. Sci. U.S.A. 85, 5693−5697 (1988). | ChemPort |
  10. Jones, P.A. et al. De novo methylation of the MyoD1 CpG island during the establishment of immortal cell lines. Proc. natn. Acad. Sci. U.S.A. 87, 6117−6121 (1990). | ChemPort |
  11. Makos, M. et al. Distinct hypermethylation patterns occur at altered chromosome loci in human lung and colon cancer. Proc. natn. Acad. Sci. U.S.A. 89, 1929−1933 (1992). | ChemPort |
  12. Sakai, T. et al. Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am. J. hum. Genet. 48, 880−888 (1991). | PubMed  | ISI | ChemPort |
  13. Oberlé, I. et al. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 253, 1097−1102 (1991). | PubMed  | ISI |
  14. Hansen, R.S., Gartler, S.M., Scott, C.R., Chen, S.-H. & Laird, D.C. Methylation analysis of CGG sites in the CpG island of the human FMR1 gene. Hum. molec. Genet. 1, 571−578 (1992). | PubMed  | ChemPort |
  15. Ottaviano, Y.L., Issa, J.-P.J., Farl, F.F., Smith, H.S., Baylim, S.B. & Davidson, N.E. Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res. 54, 2552−2555 (1994). | PubMed  | ISI | ChemPort |
  16. Greene, G.L. et al. Sequence and expression of human estrogen receptor complementary DNA. Science 231, 1150−1154 (1986). | PubMed  | ISI | ChemPort |
  17. Green, S. et al. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature 320, 134−139 (1986). | PubMed  | ISI | ChemPort |
  18. Piva, R., Gambari, R., Zorzato, F., Kumar, L. & del Senno, L. Analysis of upstream sequences of the human estrogen receptor gene. Biochem. Biophys. res. Commun. 183, 996−1002 (1992). | PubMed  | ISI | ChemPort |
  19. Colby, W.W., Chen, E.Y., Smith, D.H. & Levinson, A.D. Identification and nucleotide sequence of a human locus homologous to the v-myc oncogene of avian myelocytomatosis virus MC29. Nature 301, 722−725 (1983). | PubMed  | ISI | ChemPort |
  20. Neugut, A.I., Jacobson, J.S. & DeVivo, I. Epidemiology of colorectal adenomatous polyps. Cancer Epidemiol. Biomarkers & Prevention 2, 159−176 (1993). | ChemPort |
  21. Meggough, F., Lointier, P. & Saez, S. Sex steroid and 1,25-dihydroxyvitamin D3 receptors in human colorectal adenocarcinoma and normal mucosa. Cancer Res. 51, 1227−1233 (1991). | PubMed  | ISI | ChemPort |
  22. Dawson, P.M. et al. Oestrogen receptors in colorectal carcinoma. J. clin. Pathol. 43, 149−151 (1990). | PubMed  | ISI | ChemPort |
  23. Thomas, M.L., Xu, X., Norfleet, A.M. & Watson, C.S. The presence of functional estrogen receptors in Intestinal epithelial cells. Endocrinology 132, 426−430 (1993). | Article | PubMed  | ISI | ChemPort |
  24. Corradino, R.A., Smith, C.A., Krook, L.P. & Fullmer, C.S. Tissue-specific regulation of shell gland calbindin D28K biosynthesis byestradiol in precociously matured, vitamin D-depleted chicks. Endocrinology 132, 193−198 (1993). | Article | PubMed  | ISI | ChemPort |
  25. Arjandi, B.H., Salih, M.A., Herbert, D.C., Sims, S.H. & Kalu, D.N. Evidence for estrogen receptor-linked calcium transport in the intestine. Bone & Mineral 21, 63−74 (1993).
  26. Brommage, R., Binacua, C. & Carrie, A.L. Ovulation-associated increase in intestinal calcium absorption during the rat estrous cycle is blunted by ovariectomy. Biol. Reprod. 49, 544−548 (1993). | PubMed  | ISI | ChemPort |
  27. Watts, C.K.W., Parker, M.G. & King, R.J.B. Stable transfection of the oestrogen receptor gene into a human osteosarcoma cell line. J. steroid Biochem. 34, 483−490 (1989). | Article | PubMed  | ISI | ChemPort |
  28. Maminta, M.L., Molteni, A. & Rosen, S.T. Stable expression of the human estrogen receptor in HeLa cells by infection: effect of estrogen on cell proliferation and c-myc expression. Molec. cell. Endocrinol. 78, 61−69 (1991). | Article | PubMed  | ISI | ChemPort |
  29. Ma, Z.Q. et al. Activated estrogen receptor mediates growth arrest and differentiation of a neuroblastoma cell line. Proc. natn. Acad. Sci. U.S.A. 90, 3740−3744 (1993). | ChemPort |
  30. Garcia, M., Derocq, D., Freiss, G. & Rochefort, H. Activation of estrogen receptor transfected into a receptor-negative breast cancer cell line decreases the metastatic and invasive potential of the cells. Proc. natn. Acad. Sci. U.S.A. 89, 11538−11542 (1992). | ChemPort |
  31. Zajchowski, D.A., Sager, R. & Webster, L. Estrogen inhibits the growth of estrogen receptor-negative, but not estrogen receptor-positive, human mammary epithelial cells expressing a recombinant estrogen receptor. Cancer Res. 53, 5004−5011 (1993). | PubMed  | ISI | ChemPort |
  32. Jiang, S.-Y. & Jordan, V.C. Growth regulation of estrogen receptor-negative breast cancer cells transfected with complementary DNAs for estrogen receptor. J. natn. Cancer Inst. 84, 580−591 (1992). | ChemPort |
  33. Holliday, R. The inheritance of epigenetic defects. Science 238, 163−70 (1987). | PubMed  | ISI | ChemPort |
  34. Uehara, Y., Ono, T., Kurishita, A., Kokuryu, H. & Okada, S. Age-dependent and tissue-specific changes of DNA methylation within and around the c-fos gene in mice. Oncogene 4, 1023−1028 (1989). | PubMed  | ISI | ChemPort |
  35. Ghazi, H., Gonzales, F.A. & Jones, P.A. Methylation of CpG-island-containing genes in human sperm, fetal and adult tissues. Gene 114, 203−210 (1992). | Article | PubMed  | ISI | ChemPort |
  36. Atillasoy, E. & Holt, P.H. Gastrointestinal proliferation and aging. J. Gerontol. 48, B43−B49 (1993). | PubMed  | ISI | ChemPort |
  37. Antequera, F., Boyes, J. & Bird, A. High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines. Cell 62, 503−514 (1990). | Article | PubMed  | ISI | ChemPort |
  38. Tata, J.R., Baker, B.S., Machuca, I., Rabelo, E.M.L. & Yamauchi, K. Autoinduction of nuclear receptor genes and its significance. J. steroid Biochem. & molec. Biol. 46, 105−119 (1993). | Article | PubMed  | ChemPort |
  39. Sapolsky, R.M., Vogelman, J.H., Orentreich, N. & Altmann, J. Senescent decline in serum dehydroepiandrosterone sulfate concentrations in a population of wild baboons. J. Gerontol. 48, 196−200 (1993).
  40. Furner, S.E., Davis, F.G., Nelson, R.L. & Haenszel, W. A sase-control study of large bowel cancer and hormone exposure in women. Cancer Res. 49, 4936−4940 (1989). | PubMed  | ISI | ChemPort |
  41. Chute, C.G. et al. A prospective study of reproductive history and exogenous estrogens on the risk of colorectal cancer in women. Epidemiol. 2, 201−207 (1991). | ChemPort |
  42. Gerhardswon de Verdier, M. & London, S. Reproductive factors, exogenous female hormones, and colorectal cancer by subsite. Canc. Caus. Cont. 3, 355−360 (1992).
  43. Weigel, R.J. & deConinck, E.C. Transcriptlonal control of estrogen receptor in estrogen receptor-negative breast carcinoma. Cancer Res. 53, 3472−3474 (1993). | PubMed  | ISI | ChemPort |
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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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