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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
- 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.
- Subjects :
- 0301 basic medicine
Antineoplastic Agents, Hormonal
Transcription, Genetic
Endocrinology, Diabetes and Metabolism
Clinical Biochemistry
DNA, Recombinant
Estrogen receptor
Breast Neoplasms
Biology
Response Elements
Biochemistry
Proto-Oncogene Protein c-ets-2
03 medical and health sciences
Estrogen-related receptor alpha
0302 clinical medicine
Endocrinology
Genes, Reporter
Humans
Promoter Regions, Genetic
Molecular Biology
Conserved Sequence
Estrogen receptor beta
Base Sequence
Aromatase Inhibitors
Pioneer factor
Estrogen Receptor alpha
Cell Biology
DNA Methylation
Middle Aged
Recombinant Proteins
Neoplasm Proteins
030104 developmental biology
CpG site
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Mutation
DNA methylation
MCF-7 Cells
Cancer research
Molecular Medicine
Female
Estrogen-related receptor gamma
Estrogen receptor alpha
Dinucleoside Phosphates
Subjects
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