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The Johns Hopkins Oncology Center [J. R. G., J. G. H., R. G. L. H. C., R. X., P. M. P., N. E. D., S. B. B.] and The Brady Urological Institute [D. F. J., W. B. I.], Johns Hopkins University Medical Center, Baltimore, Maryland 21231
Expression of the Ca2+-dependent, homotypic cell:cell adhesion molecule, E-cadherin (E-cad), suppresses tumor cell invasion and metastasis in experimental tumor models. Decreased E-cad expression is common in poorly differentiated, advanced-stage carcinomas. These data implicate E-cad as an "invasion suppressor" gene. The mechanism by which E-cad is silenced in advanced stage carcinomas is unclear. In this report, we show that: (a) the 5' CpG island of E-cad is densely methylated in E-cad-negative breast and prostate carcinoma cell lines and primary breast carcinoma tissue but is unmethylated in normal breast tissue; (b) treatment with the demethylating agent, 5-aza-2'-deoxycytidine, partially restores E-cad RNA and protein levels in E-cad-negative breast and prostate carcinoma cell lines; and (c) an E-cad promoter/CAT construct is expressed in both E-cad-positive and -negative breast and prostate carcinoma cell lines, indicating that these cells have the active transcriptional machinery necessary for E-cad gene expression. Our data demonstrate that frequent loss of E-cad expression in human breast and prostate carcinomas results from hypermethylation of the E-cad promoter region.
1 This work was supported by National Cancer Institute Grants CA43318 (to J. R. G., J. G. H., H. C., and S. B. B.) and DK49043 (to R. X. and P. M. P.) and a grant from the Susan G. Komen Foundation (to R. G. L.).
2 To whom requests for reprints should be addressed, at The Johns Hopkins University Oncology Center, 424 North Bond Street, Baltimore, MD 21231. Phone: (410) 955-8506; Fax: (410) 614-9884.
Received 8/15/95. Accepted 10/ 2/95.
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H C Kim, J M D Wheeler, J C Kim, M Ilyas, N E Beck, B S Kim, K C Park, and W F Bodmer The E-cadherin gene (CDH1) variants T340A and L599V in gastric and colorectal cancer patients in Korea Gut, August 1, 2000; 47(2): 262 - 267. [Abstract] [Full Text] [PDF] |
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S. J. Nass, J. G. Herman, E. Gabrielson, P. W. Iversen, F. F. Parl, N. E. Davidson, and J. R. Graff Aberrant Methylation of the Estrogen Receptor and E-Cadherin 5' CpG Islands Increases with Malignant Progression in Human Breast Cancer Cancer Res., August 1, 2000; 60(16): 4346 - 4348. [Abstract] [Full Text] |
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R. T. Cormier and W. F. Dove Dnmt1N/+ Reduces the Net Growth Rate and Multiplicity of Intestinal Adenomas in C57BL/6-Multiple Intestinal Neoplasia (Min)/+ Mice Independently of p53 but Demonstrates Strong Synergy with the Modifier of Min 1AKR Resistance Allele Cancer Res., July 1, 2000; 60(14): 3965 - 3970. [Abstract] [Full Text] |
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J. R. Melki, P. C. Vincent, R. D. Brown, and S. J. Clark Hypermethylation of E-cadherin in leukemia Blood, May 15, 2000; 95(10): 3208 - 3213. [Abstract] [Full Text] [PDF] |
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B. A. Usmani, R. Shen, M. Janeczko, C. N. Papandreou, W.-H. Lee, W. G. Nelson, J. B. Nelson, and D. M. Nanus Methylation of the Neutral Endopeptidase Gene Promoter in Human Prostate Cancers Clin. Cancer Res., May 1, 2000; 6(5): 1664 - 1670. [Abstract] [Full Text] [PDF] |
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E. R. Fearon BRCA1 and E-Cadherin Promoter Hypermethylation and Gene Inactivation in Cancer--Association or Mechanism? J Natl Cancer Inst, April 5, 2000; 92(7): 515 - 517. [Full Text] [PDF] |
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G. Tamura, J. Yin, S. Wang, A. S. Fleisher, T. Zou, J. M. Abraham, D. Kong, K. N. Smolinski, K. T. Wilson, S. P. James, et al. E-Cadherin Gene Promoter Hypermethylation in Primary Human Gastric Carcinomas J Natl Cancer Inst, April 5, 2000; 92(7): 569 - 573. [Abstract] [Full Text] [PDF] |
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J. R. Graff, E. Gabrielson, H. Fujii, S. B. Baylin, and J. G. Herman Methylation Patterns of the E-cadherin 5' CpG Island Are Unstable and Reflect the Dynamic, Heterogeneous Loss of E-cadherin Expression during Metastatic Progression J. Biol. Chem., January 28, 2000; 275(4): 2727 - 2732. [Abstract] [Full Text] [PDF] |
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J. MacDougall and L. Matrisian Targets of extinction: identification of genes whose expression is repressed as a consequence of somatic fusion between cells representing basal and luminal mammary epithelial phenotypes J. Cell Sci., January 2, 2000; 113(3): 409 - 423. [Abstract] [PDF] |
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M von Schlippe, J. Marshall, P Perry, M Stone, A. Zhu, and I. Hart Functional interaction between E-cadherin and alphav-containing integrins in carcinoma cells J. Cell Sci., January 2, 2000; 113(3): 425 - 437. [Abstract] [PDF] |
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H. Yin and K. L. Blanchard DNA methylation represses the expression of the human erythropoietin gene by two different mechanisms Blood, January 1, 2000; 95(1): 111 - 119. [Abstract] [Full Text] [PDF] |
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L. H. Ellenson hMLH1 Promoter Hypermethylation in Microsatellite Instability-Positive Endometrial Carcinoma : Cause or Consequence? Am. J. Pathol., November 1, 1999; 155(5): 1399 - 1402. [Full Text] [PDF] |
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E. E. Cameron, S. B. Baylin, and J. G. Herman p15INK4B CpG Island Methylation in Primary Acute Leukemia Is Heterogeneous and Suggests Density as a Critical Factor for Transcriptional Silencing Blood, October 1, 1999; 94(7): 2445 - 2451. [Abstract] [Full Text] [PDF] |
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N. Fujita, S.-i. Takebayashi, K. Okumura, S. Kudo, T. Chiba, H. Saya, and M. Nakao Methylation-Mediated Transcriptional Silencing in Euchromatin by Methyl-CpG Binding Protein MBD1 Isoforms Mol. Cell. Biol., September 1, 1999; 19(9): 6415 - 6426. [Abstract] [Full Text] [PDF] |
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N. L. Tran, R. B. Nagle, A. E. Cress, and R. L. Heimark N-Cadherin Expression in Human Prostate Carcinoma Cell Lines : An Epithelial-Mesenchymal Transformation Mediating Adhesion withStromal Cells Am. J. Pathol., September 1, 1999; 155(3): 787 - 798. [Abstract] [Full Text] [PDF] |
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J. Luo, D. M. Lubaroff, and M. J. C. Hendrix Suppression of Prostate Cancer Invasive Potential and Matrix Metalloproteinase Activity by E-Cadherin Transfection Cancer Res., August 1, 1999; 59(15): 3552 - 3556. [Abstract] [Full Text] [PDF] |
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J. R. Melki, P. C. Vincent, and S. J. Clark Concurrent DNA Hypermethylation of Multiple Genes in Acute Myeloid Leukemia Cancer Res., August 1, 1999; 59(15): 3730 - 3740. [Abstract] [Full Text] [PDF] |
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L. Yuan, J. Shan, D. De Risi, J. Broome, J. Lovecchio, D. Gal, V. Vinciguerra, and H.-p. Xu Isolation of a Novel Gene, TSP50, by a Hypomethylated DNA Fragment in Human Breast Cancer Cancer Res., July 1, 1999; 59(13): 3215 - 3221. [Abstract] [Full Text] [PDF] |
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W. B. Archey, M. P. Sweet, G. C. Alig, and B. A. Arrick Methylation of CpGs as a Determinant of Transcriptional Activation at Alternative Promoters for Transforming Growth Factor-{beta}3 Cancer Res., May 1, 1999; 59(10): 2292 - 2296. [Abstract] [Full Text] [PDF] |
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E. Pötter, C. Bergwitz, and G. Brabant The Cadherin-Catenin System: Implications for Growth and Differentiation of Endocrine Tissues Endocr. Rev., April 1, 1999; 20(2): 207 - 239. [Abstract] [Full Text] |
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J. A. Efstathiou, D. Liu, J. M. D. Wheeler, H. C. Kim, N. E. Beck, M. Ilyas, A. J. Karayiannakis, N. J. McC. Mortensen, W. Kmiot, R. J. Playford, et al. Mutated epithelial cadherin is associated with increased tumorigenicity and loss of adhesion and of responsiveness to the motogenic trefoil factor 2 in colon carcinoma cells PNAS, March 2, 1999; 96(5): 2316 - 2321. [Abstract] [Full Text] [PDF] |
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E. Ruijter, C. van de Kaa, G. Miller, D. Ruiter, F. Debruyne, and J. Schalken Molecular Genetics and Epidemiology of Prostate Carcinoma Endocr. Rev., February 1, 1999; 20(1): 22 - 45. [Abstract] [Full Text] |
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K. E. Bachman, J. G. Herman, P. G. Corn, A. Merlo, J. F. Costello, W. K. Cavenee, S. B. Baylin, and J. R. Graff Methylation-associated Silencing of the Tissue Inhibitor of Metalloproteinase-3 Gene Suggests a Suppressor Role in Kidney, Brain, and Other Human Cancers Cancer Res., February 1, 1999; 59(4): 798 - 802. [Abstract] [Full Text] [PDF] |
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I. H. N. Wong, Y. M. Dennis Lo, J. Zhang, C.-T. Liew, M. H. L. Ng, N. Wong, P. B. S. Lai, W. Y. Lau, N. M. Hjelm, and P. J. Johnson Detection of Aberrant p16 Methylation in the Plasma and Serum of Liver Cancer Patients Cancer Res., January 1, 1999; 59(1): 71 - 73. [Abstract] [Full Text] [PDF] |
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S. Y. Leung, S. T. Yuen, L. P. Chung, K. M. Chu, A. S. Y. Chan, and J. C. I. Ho hMLH1 Promoter Methylation and Lack of hMLH1 Expression in Sporadic Gastric Carcinomas with High-Frequency Microsatellite Instability Cancer Res., January 1, 1999; 59(1): 159 - 164. [Abstract] [Full Text] [PDF] |
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K. B. Hoover, S.-Y. Liao, and P. J. Bryant Loss of the Tight Junction MAGUK ZO-1 in Breast Cancer : Relationship to Glandular Differentiation and Loss ofHeterozygosity Am. J. Pathol., December 1, 1998; 153(6): 1767 - 1773. [Abstract] [Full Text] [PDF] |
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