Estrogen Receptor Alpha Mutations in Breast Cancer Cells Cause Gene Expression Changes through Constant Activity and Secondary Effects.
Spencer ArnesenZannel BlanchardMichelle M WilliamsKristofer C BerrettZheqi LiSteffi OesterreichJennifer K RicherJason GertzPublished in: Cancer research (2020)
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.
Keyphrases
- estrogen receptor
- wild type
- breast cancer cells
- gene expression
- endoplasmic reticulum
- transcription factor
- dna binding
- dna methylation
- genome wide
- newly diagnosed
- young adults
- end stage renal disease
- cell cycle arrest
- diabetic retinopathy
- endoplasmic reticulum stress
- peritoneal dialysis
- single molecule
- heat shock
- diabetic rats
- heat stress
- copy number
- binding protein