Single CpG site methylation controls estrogen receptor gene transcription and correlates with hormone therapy resistance

Publication date: Available online 12 April 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Kouki Tsuboi, Takamasa Nagatomo, Tatsuyuki Gohno, Toru Higuchi, Shunta Sasaki, Natsu Fujiki, Masafumi Kurosumi, Hiroyuki Takei, Yuri Yamaguchi, Toshifumi Niwa, Shin-ichi Hayashi
Hormone therapy is the most effective treatment for patients with estrogen receptor α-positive breast cancers. However, although resistance occurs during treatment in some cases and often reflects changed estrogen receptor α status, the relationship between changes in estrogen receptor α expression and resistance to therapy is poorly understood. In this study, we identified a mechanism for altered estrogen receptor α expression during disease progression and acquired hormone therapy resistance in aromatase inhibitor-resistant breast cancer cell lines. Subsequently, we investigated promoter switching and DNA methylation status of the estrogen receptor α promoter, and found marked changes of methylation at a single CpG site (CpG4) in resistant cells. In addition, luciferase reporter assays showed reduced transcriptional activity from this methylated CpG site. This CpG region was also completely conserved among species, suggesting that it acts as a methylation-sensitive Ets-2 transcription factor binding site, as confirmed using chromatin immunoprecipitation assays. In estrogen receptor α-positive tumors, CpG4 methylation levels were inversely correlated with estrogen receptor α expression status, suggesting that single CpG site plays an important role in the regulation of estrogen receptor α transcription.



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