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


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Type
Article
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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.

Publication Date
2018-11-20
Online Publication Date
2018-11-20
Acceptance Date
2018-11-16
Keywords
Estrogen, Estrogen Receptor, MCF7, breast Cancer, chromosomes, computational biology, endocrine, gene expression, human, systems biology, Base Sequence, Binding Sites, Estradiol, Estrogen Receptor alpha, Female, Gene Expression Regulation, Neoplastic, Genome, Human, Genome-Wide Association Study, Humans, MCF-7 Cells, Neoplasm Proteins, Promoter Regions, Genetic, Protein Binding, Receptors, CXCR, Signal Transduction, Sorting Nexins, Trefoil Factor-1
Journal Title
Elife
Journal ISSN
2050-084X
2050-084X
Volume Title
7
Publisher
eLife Sciences Publications, Ltd
Sponsorship
Breast Cancer Campaign (2012NovemberPR042)
Cancer Research UK (C14303/A17197)
Alan Turing Institute (Unknown)
Cancer Research UK (A19274)