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Updated: Nov 30, 2025
Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
Published on: February 21, 2014
Estrogen Receptor Alpha Mutations in Breast Cancer Cells Cause Gene Expression Changes through Constant Activity and
Spencer Arnesen1,2, Zannel Blanchard1,2, Michelle M Williams3
1Department of Oncological Sciences, University of Utah, Salt Lake City, Utah.
Abstract:
While breast cancer patients with tumors that express estrogen receptor α (ER) generally respond well to hormone therapies that block ER activity, a significant number of patients relapse. Approximately 30% of these recurrences harbor activating mutations in the ligand binding domain (LBD) of ER, which have been shown to confer ligand-independent function. However, much is still unclear regarding the effect of mutant ER beyond its estrogen independence. To investigate the molecular effects of mutant ER, we developed multiple isogenic ER-mutant cell lines for the most common LBD mutations, Y537S and D538G. These mutations induced differential expression of thousands of genes, the majority of which were mutant allele specific and were not observed upon estrogen treatment of wild-type (WT) cells. These mutant-specific genes showed consistent differential expression across ER-mutant lines developed in other laboratories. WT cells with long-term estrogen exposure only exhibited some of these transcriptional changes, suggesting that mutant ER causes novel regulatory effects that are not simply due to constant activity. While ER mutations exhibited minor effects on ER genomic binding, with the exception of ligand independence, ER mutations conferred substantial differences in chromatin accessibility. Mutant ER was bound to approximately a quarter of mutant-enriched accessible regions that were enriched for other DNA binding factors, including FOXA1, CTCF, and OCT1. Overall, our findings indicate that mutant ER causes several consistent effects on gene expression, both indirectly and through constant activity. SIGNIFICANCE: This study demonstrates the multiple roles of mutant ER in breast cancer progression, including constant ER activity and secondary regulatory effects on gene expression and chromatin accessibility. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/3/539/F1.large.jpg.See related commentary by Hermida-Prado and Jeselsohn, p. 537 See related article by Williams and colleagues, p. 732.
Insights
Estrogen receptor alpha (ER) mutations in breast cancer drive tumor recurrence by altering gene expression and chromatin accessibility, independent of estrogen. These findings reveal new therapeutic targets beyond hormone blockade.
Area of Science:
- Molecular Biology
- Genomics
- Cancer Research
Background:
- Estrogen receptor alpha (ER)-positive breast cancer patients often relapse despite hormone therapy.
- Activating mutations in the ER ligand-binding domain (LBD) are found in ~30% of recurrences, conferring ligand-independent function.
- The full molecular impact of these ER mutations beyond estrogen independence remains largely unknown.
Purpose of the Study:
- To investigate the comprehensive molecular effects of common ER LBD mutations (Y537S, D538G).
- To understand how mutant ER influences gene expression and chromatin accessibility.
- To elucidate the roles of mutant ER in breast cancer progression.
Main Methods:
- Development of isogenic ER-mutant cell lines (Y537S, D538G).
- Differential gene expression analysis.
- Chromatin accessibility profiling and assessment of ER genomic binding.
Main Results:
- ER mutations induced thousands of unique, mutant allele-specific gene expression changes.
- Mutant ER significantly altered chromatin accessibility, with mutant ER binding enriched in accessible regions.
- Mutant ER binding sites overlapped with other key DNA-binding factors like FOXA1, CTCF, and OCT1.
- Transcriptional changes were not solely due to constant ER activity, suggesting secondary regulatory effects.
Conclusions:
- Mutant ER drives breast cancer progression through both constant activity and novel regulatory effects on gene expression.
- Mutant ER significantly impacts chromatin accessibility, influencing the broader genomic landscape.
- These findings highlight the multifaceted roles of mutant ER and suggest new therapeutic avenues.
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