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Updated: Aug 22, 2026
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Discovery of estrogen receptor alpha target genes and response elements in breast tumor cells
Chin-Yo Lin1, Anders Ström, Vinsensius Berlian Vega
1Genome Institute of Singapore, Singapore 117528. lincy@gis.a-star.edu.sg
Background:
Estrogens and their receptors are important in human development, physiology and disease. In this study, we utilized an integrated genome-wide molecular and computational approach to characterize the interaction between the activated estrogen receptor (ER) and the regulatory elements of candidate target genes.
Results:
Of around 19,000 genes surveyed in this study, we observed 137 ER-regulated genes in T-47D cells, of which only 89 were direct target genes. Meta-analysis of heterogeneous in vitro and in vivo datasets showed that the expression profiles in T-47D and MCF-7 cells are remarkably similar and overlap with genes differentially expressed between ER-positive and ER-negative tumors. Computational analysis revealed a significant enrichment of putative estrogen response elements (EREs) in the cis-regulatory regions of direct target genes. Chromatin immunoprecipitation confirmed ligand-dependent ER binding at the computationally predicted EREs in our highest ranked ER direct target genes, NRIP1, GREB1 and ABCA3. Wider examination of the cis-regulatory regions flanking the transcriptional start sites showed species conservation in mouse-human comparisons in only 6% of predicted EREs.
Conclusions:
Only a small core set of human genes, validated across experimental systems and closely associated with ER status in breast tumors, appear to be sufficient to induce ER effects in breast cancer cells. That cis-regulatory regions of these core ER target genes are poorly conserved suggests that different evolutionary mechanisms are operative at transcriptional control elements than at coding regions. These results predict that certain biological effects of estrogen signaling will differ between mouse and human to a larger extent than previously thought.
Insights
Estrogen receptor (ER) interactions with genes are crucial for development and disease. This study identified a core set of direct ER target genes, revealing poor evolutionary conservation in their regulatory regions, suggesting species-specific estrogen signaling effects.
Area of Science:
- Genomics
- Molecular Biology
- Computational Biology
Background:
- Estrogens and their receptors (ER) play vital roles in human development, physiology, and disease.
- Understanding ER interactions with gene regulatory elements is critical for disease research.
Purpose of the Study:
- To characterize the interaction between activated ER and regulatory elements of candidate target genes using an integrated molecular and computational approach.
Main Methods:
- Genome-wide molecular and computational analysis of gene regulation.
- Meta-analysis of in vitro and in vivo datasets.
- Chromatin immunoprecipitation to confirm ER binding sites.
Main Results:
- Identified 137 ER-regulated genes, with 89 direct targets in T-47D cells.
- Found significant enrichment of estrogen response elements (EREs) in cis-regulatory regions of direct target genes.
- Confirmed ligand-dependent ER binding at predicted EREs in NRIP1, GREB1, and ABCA3.
- Observed poor species conservation (6%) of predicted EREs between mouse and human.
Conclusions:
- A small set of core ER target genes, validated across systems and linked to ER status in breast tumors, drives ER effects in breast cancer cells.
- Poor conservation of cis-regulatory regions suggests distinct evolutionary mechanisms compared to coding regions.
- Estrogen signaling effects may differ significantly between mouse and human models.
