Review of: Methylation of estrogen receptor β promoter correlates with loss of ER-β expression in mammary carcinoma and is an early indication marker in premalignant lesions

Abstract

of (cid:1) promoter correlates with loss of ER- (cid:1) expression in mammary carcinoma and is an early indication marker in premalignant lesions. Endocrine-Related Cancer 2005; 12 : 903–916. Abstract of the original article The function of estrogen receptor beta (ER- (cid:1) ) in mammary tissue is not completely understood. While early observations were often conflicting, more recent data suggest an important role as a tumor-suppressor gene. A decrease of ER- (cid:1) expression has been observed in ductal carcinoma in situ and invasive carcinomas as compared with benign mammary epithelial cells. The loss of ER- (cid:1) resulted in abnormal growth of mammary epithelial cells. We have previously shown that the mRNA expression of the ER- (cid:1) gene is almost totally suppressed in breast carcinomas from patients with a poor prognosis. Here we analyzed whether methylation changes in the different promoters of ER- (cid:1) are responsible for the loss of expression of the gene. A methylation assay with high specificity and sensitivity was developed, and a panel of breast tissue samples ( n (cid:2) 175) was characterized for methylation status. In contrast to benign breast, more than two-thirds of invasive breast cancers showed a high degree of methylation. Importantly, increased methylation was also detectable in numerous premalignant lesions. By analysis of breast tumors, previously characterized by gene-expression profiling, methylation was predominantly detected in a subgroup of patients with an unfavorable prognosis, suggesting a possible prognostic value of the ER- (cid:1) methylation status. We also investigated the structural characteristics of the two ER- (cid:1) promoters, which were both found to be closely associated with a second, downstream, localized and opposite-oriented promoter. However, we could not detect endogenous antisense RNA transcribed from these promoters, which may be involved in epigenetic gene silencing. We also failed to induce ER- (cid:1) promoter methylation by expressing siRNAs in cell lines. Interestingly, by comparing the promoter sequences of ER- (cid:1) with other genes known to be epigenetically inactivated in breast cancers, we iden-tified a sequence motif possibly involved in promoter methylation.