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

• Published in: Breast cancer online Vol. 9; no. 9; p. 1
• Main Authors: Skliris, G P, Murphy, L C
• Format: Journal Article
• Language: English
• Published: Cambridge Cambridge University Press 01-09-2006
• Subjects: Breast cancer; Cells; Investigations; Tumors
• ISSN: 1470-9031

Citation of original article: A. Rody, U. Holtrich, C. Solbach, K. Kourtis, G. von Minckwitz, K. Engels, S. Kissler, R. Gätje, T. Karn, M. Kaufmann. 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. Endocrine-Related Cancer 2005; 12: 903-916. Abstract of the original article The function of estrogen receptor beta (ER-Β) 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-Β expression has been observed in ductal carcinoma in situ and invasive carcinomas as compared with benign mammary epithelial cells. The loss of ER-Β resulted in abnormal growth of mammary epithelial cells. We have previously shown that the mRNA expression of the ER-Β 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-Β 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 = 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-Β methylation status. We also investigated the structural characteristics of the two ER-Β 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-Β promoter methylation by expressing siRNAs in cell lines. Interestingly, by comparing the promoter sequences of ER-Β with other genes known to be epigenetically inactivated in breast cancers, we identified a sequence motif possibly involved in promoter methylation. [PUBLICATION ABSTRACT]