© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 5, 384-390,
March 6, 2002
© 2002 Oxford University Press
ARTICLE |
Methylation and Inactivation of Estrogen, Progesterone, and Androgen Receptors in Prostate Cancer
Affiliations of authors: M. Sasaki, Y. Tanaka, G. Perinchery, A. Dharia, I. Kotcherguina, R. Dahiya, Department of Urology, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco; S. Fujimoto, Department of Obstetrics and Gynecology, School of Medicine, Hokkaido University, Kitaku, Sapporo, Japan.
Correspondence to: Rajvir Dahiya, Ph.D., Urology Research Center (112F), University of California, San Francisco, and Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA 94121 (e-mail: Urologylab{at}aol.com).
Background: Prostate cancer development is initially steroid hormone dependent. Estrogen receptors (ERs), androgen receptors (ARs), and progesterone receptors (PRs) have been identified in normal and cancerous prostate tissues. We investigated whether the promoter regions of these steroid receptor genes are methylated and inactivated in prostate cancer cells and tissues. Methods: The expression and promoter methylation status of three ER
isoforms (ER-A, ER-B, and ER-C), ER
, two PR isoforms (PR-A and PR-B), and AR were investigated in five prostate cancer cell lines (ND1, DU145, PC3, LNCaP, and DUPro) and in pairs of normal and cancerous prostate tissues from 38 patients with prostate cancer. Methylation-specific polymerase chain reaction, reverse transcription–polymerase chain reaction, and 5` rapid amplification of complementary DNA ends were used. All statistical tests were two-sided. Results: ER-C was expressed in all cell lines, but ER-A and ER-B were not expressed in any cell line. ER-A and ER-B promoters were methylated, but ER-C was unmethylated. Promoters for ER, AR, PR-A, and PR-B were methylated and thus inactivated in some cell lines but not in others. Treating cells with the demethylating reagent 5-aza-2`-deoxycytidine restored expression of all steroid receptor genes with previously methylated promoters. All 38 pairs of cancer and normal tissues had unmethylated ER-C promoters. Thirty-six (95%) of 38 cancers had methylated ER-A, 35 (92%) of 38 cancers had methylated ER-B, but all normal tissues had unmethylated ER-A and ER-B (both P<.001). ER was methylated in 30 (79%) of 38 cancers but unmethylated in all normal tissues. AR was methylated in three (8%) of 38 cancers but unmethylated in all normal tissues. PR-A and PR-B were unmethylated in all tissues. Conclusion: Certain steroid receptor genes appear to be inactivated by CpG methylation in prostate cancer tissue and cell lines.
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