Genome-wide Estrogen Receptor-α activation is sustained, not cyclical

Abstract
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Abstract

Estrogen Receptor-alpha (ER) drives 75% of breast cancers. Stimulation of the ER by estra-2-diol forms a transcriptionally-active chromatin-bound complex. Previous studies reported that ER binding follows a cyclical pattern. However, most studies have been limited to individual ER target genes and without replicates. Thus, the robustness and generality of ER cycling are not well understood. We present a comprehensive genome-wide analysis of the ER after activation, based on 6 replicates at 10 time-points, using our method for precise quantification of binding, Parallel-Factor ChIP-seq. In contrast to previous studies, we identified a sustained increase in affinity, alongside a class of estra-2-diol independent binding sites. Our results are corroborated by quantitative re-analysis of multiple independent studies. Our new model reconciles the conflicting studies into the ER at the TFF1 promoter and provides a detailed understanding in the context of the ER's role as both the driver and therapeutic target of breast cancer.

Data availability

Sequencing data have been deposited in GEO under accession code GSE119057.

The following data sets were generated

(2018) Genome-wide Estrogen Receptor-alpha activation time-course
Gene Expression Omnibus, GSE119057.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE119057

Article and author information

Author details

Andrew N Holding

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom

For correspondence
andrew.holding@cruk.cam.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8459-7048
Amy E Cullen

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Florian Markowetz

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom

Competing interests
The authors declare that no competing interests exist.

Funding

Cancer Research UK (C14303/A17197)

Florian Markowetz

Breast Cancer Now (2012NovPR042)

Florian Markowetz

Cancer Research UK (C60571/A24631)

Andrew N Holding

Cancer Research UK (A19274)

Florian Markowetz

Alan Turing Institute (EPSRC grant EP/N510129/129/1)

Andrew N Holding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.