Tamoxifen-resistant breast cancers show less frequent methylation of the estrogen receptor β but not the estrogen receptor α gene
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No reports have examined the association between tamoxifen resistance and the methylation of the estrogen receptor (ER) α and β genes. Therefore we investigated the methylation patterns of the ER genes in the tamoxifen-resistant tumors. We used bisulfite genomic sequencing and reverse transcriptase PCR to determine the methylation patterns and mRNA expression of the two ER genes from control (n=68) and tamoxifen-resistant tissues (n=34) chosen by an age-matched sampling method. Bisulfite genomic sequencing allowed us to reveal the methylation of the ERα gene in 15 of the control tumors (22.1%) and in 11 tumors of the resistant group (32.4%). The methylation of ERβ was observed in 40 control tumors (58.8%) and in 8 recurrent tumors (23.5%). The methylation rate of the ERβ but not the ERα in the control group was significantly higher than in its counterpart (ERα, P=0.261; ERβ, P=0.001). Among the methylated tumors mean methylation density of ERα and ERβ in the resistant cases was significantly elevated (ERα, P=0.014; ERβ, P<0.001). Furthermore, the expression rate of ERβ mRNA was higher among the tumor in the resistant group than in the control with marginal significance (77.8% vs. 38.1%, P=0.109). Additionally, in the cancers from the resistant cases, the cells showed a higher percentage of positive staining for Ki67 than those from the control group (P=0.001). Our study indicates that there is an inverse relationship between the methylation rate of the ERβ gene and tamoxifen resistance. The tamoxifen-resistant tumors showed more dense methylation of the ERβ gene than control tumors. Although the number of case samples was limited, our results support the hypothesis that hypermethylation of the ERβ gene negatively affects the development of tamoxifen resistance.
KeywordsEstrogen receptor α Estrogen receptor β Methylation Tamoxifen resistance
Cytosine guanine dinucleotide
This work was supported by the National Cancer Center Grant.
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