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¹ Department of Gynecology, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
² German Breast Group, Schleussnerstrasse 42, 63263 Neu-Isenburg/Frankfurt, Germany
³ Department of Pathology, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany

(Requests for offprints should be addressed to T Karn; Email: t.karn{at}em.uni-frankfurt.de)

The function of estrogen receptor beta (ER-ß) 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-ß expression has been observed in ductal carcinoma in situ and invasive carcinoma as compared with benign mammary epithelial cells. The loss of ER-ß resulted in abnormal growth of mammary epithelial cells. We have previously shown that the mRNA expression of the ER-ß 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-ß 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-ß methylation status. We also investigated the structural characteristics of the two ER-ß 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-ß promoter methylation by expressing siRNAs in cell lines. Interestingly, by comparing the promoter sequences of ER-ß with other genes known to be epigenetically inactivated in breast cancers, we identified a sequence motif possibly involved in promoter methylation.

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