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

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

Authors :
Kouki Tsuboi
Natsu Fujiki
Hiroyuki Takei
Shin Ichi Hayashi
Tatsuyuki Gohno
Toshifumi Niwa
Takamasa Nagatomo
Yuri Yamaguchi
Masafumi Kurosumi
Toru Higuchi
Shunta Sasaki
Source :
The Journal of Steroid Biochemistry and Molecular Biology. 171:209-217
Publication Year :
2017
Publisher :
Elsevier BV, 2017.

Abstract

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 are 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.

Details

ISSN :
09600760
Volume :
171
Database :
OpenAIRE
Journal :
The Journal of Steroid Biochemistry and Molecular Biology
Accession number :
edsair.doi.dedup.....c6c513511f36b063547bccdf7d0db1bd
Full Text :
https://doi.org/10.1016/j.jsbmb.2017.04.001