Frequent methylation of estrogen receptor in prostate cancer : Correlation with tumor progression

• Published in: Cancer research (Chicago, Ill.) Vol. 60; no. 3; pp. 702 - 706
• Main Authors: LI, L.-C, CHUI, R, NAKAJIMA, K, BONG RYOUL OH, AU, H. C, DAHIYA, R
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.2000
• Subjects: Biological and medical sciences; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA Methylation; Humans; Male; Malformations of the urinary system; Medical sciences; Nephrology. Urinary tract diseases; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptors, Estrogen - genetics; RNA, Messenger - analysis; Tumor Cells, Cultured; Urinary tract. Prostate gland; Human; Urinary system disease; Prostate disease; Pathogenesis; Tumoral tissue; Estrogen; Malignant tumor; DNA; Established cell line; Benign neoplasm; Methylation; Male genital diseases; Prostate; Hormonal receptor
• ISSN: 0008-5472; 1538-7445

Prior studies have shown that the estrogen receptor (ER) gene is down-regulated in prostate cancer, but the mechanism of its inactivation is not known. We hypothesize that inactivation of the ER gene in prostate cancer is through promoter methylation. To test this hypothesis, we investigated the methylation status of the ER gene in prostate cancer cell lines, prostate cancer, and benign prostatic hyperplasia (BPH) tissues samples using the bisulfite genomic sequencing method. Our results show that the ER gene promoter was methylated in 100% (six of six) of the prostate cancer cell lines tested and all were accompanied by loss of ER mRNA expression. Treatment of these cell lines with demethylating agent 5-aza-2'-deoxycytidine restored ER mRNA expression in all of the ER-negative cell lines. In addition, elevated expression of DNA methyltransferase mRNA was found in all of the prostate cancer cell lines. Of the prostate tissue samples analyzed, 60% (6 of 10) in the BPH samples, 80% (8 of 10) in the low-grade cancer samples (grades I and II), and 95% (20 of 21) in the high-grade cancer samples (grades III-V) exhibited promoter methylation of the ER gene. The overall methylation levels in the cancer samples were higher than that in the BPH samples. The differences between the high-grade cancer samples and BPH samples were significant at all CpG sites. Only at three CpG sites were the differences significant between the low-grade cancer samples and BPH samples. This study presents the first evidence that ER gene is transcriptionally inactivated by DNA methylation in prostate cancer. Our data suggest that ER may be involved in the pathogenesis of prostate cancer, as well as BPH.