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

Elife. 2018 Nov 20;7:e40854. doi: 10.7554/eLife.40854.

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.

Keywords: Estrogen; Estrogen Receptor; MCF7; breast Cancer; chromosomes; computational biology; endocrine; gene expression; human; systems biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Binding Sites
  • Estradiol / metabolism
  • Estradiol / pharmacology*
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genome, Human*
  • Genome-Wide Association Study
  • Humans
  • MCF-7 Cells
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Receptors, CXCR / genetics
  • Receptors, CXCR / metabolism
  • Signal Transduction
  • Sorting Nexins / genetics
  • Sorting Nexins / metabolism
  • Trefoil Factor-1 / genetics*

Substances

  • ACKR3 protein, human
  • Estrogen Receptor alpha
  • GREB1 protein, human
  • Neoplasm Proteins
  • Receptors, CXCR
  • Sorting Nexins
  • TFF1 protein, human
  • Trefoil Factor-1
  • estrogen receptor alpha, human
  • Estradiol