© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 10, 826-832,
May 17, 2000
© 2000 Oxford University Press
REPORTS |
Methylation and Silencing of the Retinoic Acid Receptor-ß2 Gene in Breast Cancer
Affiliations of authors: M. Widschwendter, J. Berger, M. Hermann, H. M. Müller, A. Widschwendter, B. Abendstein, A. G. Zeimet, G. Daxenbichler, C. Marth (Department of Obstetrics and Gynecology), A. Amberger (D. Swarovski Research Laboratory, Department of Transplantation Surgery), University of Innsbruck, Austria; M. Zeschnigk, Department of Human Genetics, University of Essen, Germany.
Correspondence to: Martin Widschwendter, M.D., Department of Obstetrics and Gynecology, University of Innsbruck, Anichstr. 35 A-6020 Innsbruck, Austria (e-mail: Martin.Widschwendter{at}uklibk.ac.at).
Background: A growing body of evidence supports the hypotheses that the retinoic acid receptor ß2 (RAR-ß2) gene is a tumor suppressor gene and that the chemopreventive effects of retinoids are due to induction of RAR-ß2. RAR-ß2 expression is reduced in many malignant tumors, and we examined whether methylation of RAR-ß2 could be responsible for this silencing. Methods: RAR-ß2 expression was studied by reverse transcription–polymerase chain reaction (RT–PCR) analysis in eight breast cancer cell lines that were either treated with the demethylating agent 5-aza-2'-deoxycytidine and subsequently with all-trans-retinoic acid (ATRA) or left untreated. Sodium bisulfite genomic sequencing was used to determine the locations of 5-methylcytosines in the RAR-ß2 genes of three of these cell lines. In 16 breast cancer biopsy specimens and non-neoplastic breast tissue, methylation-specific PCR was used to determine the methylation status of RAR-ß2, and, in 13 of the specimens, RT–PCR analysis was used to detect RAR-ß2 expression. Results: Cell lines SK-BR-3, T-47D, ZR-75-1, and MCF7 exhibited expression of RAR-ß2 only after demethylation and treatment with ATRA. The first exon expressed in the RAR-ß2 transcript was methylated in cell lines ZR-75-1 and SK-BR-3. Six breast cancer specimens showed methylation in the same region of the gene. No expression of RAR-ß2 was found in any grade III lesion. An inverse association between methylation and gene expression was found in all grade II lesions. The RAR-ß2 gene from non-neoplastic breast tissue was unmethylated and expressed. Conclusions: Methylation of the RAR-ß2 gene may be an initial step in breast carcinogenesis; treatment of cancer patients with demethylating agents followed by retinoic acid may offer a new therapeutic modality.
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|
|
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|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
S. Dhar, R. Bhargava, M. Yunes, B. Li, J. Goyal, S. P. Naber, D. E. Wazer, and V. Band Analysis of Normal Epithelial Cell Specific-1 (NES1)/Kallikrein 10 mRNA Expression by in Situ Hybridization, a Novel Marker for Breast Cancer Clin. Cancer Res., November 1, 2001; 7(11): 3393 - 3398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
M. I. Dawson, P. D. Hobbs, V. J. Peterson, M. Leid, C. W. Lange, K.-C. Feng, G.-q. Chen, J. Gu, H. Li, S. K. Kolluri, et al. Apoptosis Induction in Cancer Cells by a Novel Analogue of 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic Acid Lacking Retinoid Receptor Transcriptional Activation Activity Cancer Res., June 1, 2001; 61(12): 4723 - 4730. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F Costello and C. Plass Methylation matters J. Med. Genet., May 1, 2001; 38(5): 285 - 303. [Abstract] [Full Text]
|
|
|
|
|
|
R. Dammann, G. Yang, and G. P. Pfeifer Hypermethylation of the CpG Island of Ras Association Domain Family 1A (RASSF1A), a Putative Tumor Suppressor Gene from the 3p21.3 Locus, Occurs in a Large Percentage of Human Breast Cancers Cancer Res., April 1, 2001; 61(7): 3105 - 3109. [Abstract] [Full Text]
|
|
|
|
|
|
M. T. Hartsough, S. E. Clare, M. Mair, A. G. Elkahloun, D. Sgroi, C. K. Osborne, G. Clark, and P. S. Steeg Elevation of Breast Carcinoma Nm23-H1 Metastasis Suppressor Gene Expression and Reduced Motility by DNA Methylation Inhibition Cancer Res., March 1, 2001; 61(5): 2320 - 2327. [Abstract] [Full Text]
|
|
|
|
|
|
A. K. Virmani, C. Muller, A. Rathi, S. Zoechbauer-Mueller, M. Mathis, and A. F. Gazdar Aberrant Methylation during Cervical Carcinogenesis Clin. Cancer Res., March 1, 2001; 7(3): 584 - 589. [Abstract] [Full Text]
|
|
|
|
|
|
R. Pili, M. P. Kruszewski, B. W. Hager, J. Lantz, and M. A. Carducci Combination of Phenylbutyrate and 13-cis Retinoic Acid Inhibits Prostate Tumor Growth and Angiogenesis Cancer Res., February 1, 2001; 61(4): 1477 - 1485. [Abstract] [Full Text]
|
|
|
|
|
|
Q. Yang, I. Mori, L. Shan, M. Nakamura, Y. Nakamura, H. Utsunomiya, G. Yoshimura, T. Suzuma, T. Tamaki, T. Umemura, et al. Biallelic Inactivation of Retinoic Acid Receptor {beta}2 Gene by Epigenetic Change in Breast Cancer Am. J. Pathol., January 1, 2001; 158(1): 299 - 303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Virmani, A. Rathi, S. Zochbauer-Muller, N. Sacchi, Y. Fukuyama, D. Bryant, A. Maitra, S. Heda, K. M. Fong, F. Thunnissen, et al. Promoter Methylation and Silencing of the Retinoic Acid Receptor-{beta} Gene in Lung Carcinomas J Natl Cancer Inst, August 16, 2000; 92(16): 1303 - 1307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Sporn Retinoids and Demethylating Agents-- Looking for Partners J Natl Cancer Inst, May 17, 2000; 92(10): 780 - 781. [Full Text] [PDF]
|
|