Evaluating hormone responses in Esr1-wildtype and mutant mammary luminal cells [RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE186453 | GEO | 2023/05/07
REPOSITORIES: GEO
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Project description:Estrogen receptor alpha (ESR1) mutations have been identified in hormone therapy resistant breast cancer and primary endometrial cancer. Analyses in breast cancer suggests that mutant ESR1 exhibits estrogen independent activity. In endometrial cancer, ESR1 mutations are associated with worse outcomes and less obesity, however experimental investigation of these mutations has not been performed. Using a unique CRISPR/Cas9 strategy, we introduced the D538G mutation, a common endometrial cancer mutation that alters the ligand binding domain of ESR1, while epitope tagging the endogenous locus. We discovered estrogen-independent mutant ESR1 genomic binding that is significantly altered from wildtype ESR1. The D538G mutation impacted expression, including a large set of non-estrogen regulated genes, and chromatin accessibility, with most affected loci bound by mutant ESR1. Mutant ESR1 is unique from constitutive ESR1 activity as mutant-specific changes are not recapitulated with prolonged estrogen exposure. Overall, D538G mutant ESR1 confers estrogen-independent activity while causing additional regulatory changes in endometrial cancer cells that are distinct from breast cancer cells.
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Project description:Estrogen receptor alpha (ESR1) mutations have been identified in hormone therapy resistant breast cancer and primary endometrial cancer. Analyses in breast cancer suggests that mutant ESR1 exhibits estrogen independent activity. In endometrial cancer, ESR1 mutations are associated with worse outcomes and less obesity, however experimental investigation of these mutations has not been performed. Using a unique CRISPR/Cas9 strategy, we introduced the D538G mutation, a common endometrial cancer mutation that alters the ligand binding domain of ESR1, while epitope tagging the endogenous locus. We discovered estrogen-independent mutant ESR1 genomic binding that is significantly altered from wildtype ESR1. The D538G mutation impacted expression, including a large set of non-estrogen regulated genes, and chromatin accessibility, with most affected loci bound by mutant ESR1. Mutant ESR1 is unique from constitutive ESR1 activity as mutant-specific changes are not recapitulated with prolonged estrogen exposure. Overall, D538G mutant ESR1 confers estrogen-independent activity while causing additional regulatory changes in endometrial cancer cells that are distinct from breast cancer cells.
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Project description:Estrogen receptor alpha (ESR1) mutations have been identified in hormone therapy resistant breast cancer and primary endometrial cancer. Analyses in breast cancer suggests that mutant ESR1 exhibits estrogen independent activity. In endometrial cancer, ESR1 mutations are associated with worse outcomes and less obesity, however experimental investigation of these mutations has not been performed. Using a unique CRISPR/Cas9 strategy, we introduced the D538G mutation, a common endometrial cancer mutation that alters the ligand binding domain of ESR1, while epitope tagging the endogenous locus. We discovered estrogen-independent mutant ESR1 genomic binding that is significantly altered from wildtype ESR1. The D538G mutation impacted expression, including a large set of non-estrogen regulated genes, and chromatin accessibility, with most affected loci bound by mutant ESR1. Mutant ESR1 is unique from constitutive ESR1 activity as mutant-specific changes are not recapitulated with prolonged estrogen exposure. Overall, D538G mutant ESR1 confers estrogen-independent activity while causing additional regulatory changes in endometrial cancer cells that are distinct from breast cancer cells.
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Project description:While breast cancer patients with tumors that express estrogen receptor α (ER) generally respond well to hormone therapies that block ER’s actions, a significant number relapse. Approximately 30% of these recurrences harbor activating mutations in ER’s ligand binding domain. ER mutations have been shown to confer ligand-independent function to ER; however, much is still unclear regarding the effect of mutant ER beyond its estrogen independence. To investigate mutant ER’s molecular effects, we developed multiple isogenic ER mutant cell lines for the two most common ER ligand binding domain mutations, Y537S and D538G. We found that these mutations induce differential expression of thousands of genes, the majority of which are specific to one or the other mutation and are not observed upon estrogen treatment of wildtype cells. The mutant-specific genes show consistent differential expression across ER mutant lines developed in other laboratories. The observed gene expression changes cannot be explained by constitutive ER activity alone, as wildtype cells with long term estrogen exposure only exhibit some of these transcriptional changes, suggesting that mutant ER causes novel regulatory effects that are not simply due to constant activity. While ER mutations have minor effects on ER genomic binding, with the exception of ligand independence, we observed substantial differences in chromatin accessibility due to ER mutations. Mutant ER is bound to approximately a quarter of mutant-enriched accessible regions that are enriched for other DNA binding factors including FOXA1, CTCF, and OCT1. Our findings indicate that mutant ER causes several consistent effects on gene expression both indirectly and through constant activity.
2020-04-08 | GSE148277 | GEO
Project description:While breast cancer patients with tumors that express estrogen receptor α (ER) generally respond well to hormone therapies that block ER’s actions, a significant number relapse. Approximately 30% of these recurrences harbor activating mutations in ER’s ligand binding domain. ER mutations have been shown to confer ligand-independent function to ER; however, much is still unclear regarding the effect of mutant ER beyond its estrogen independence. To investigate mutant ER’s molecular effects, we developed multiple isogenic ER mutant cell lines for the two most common ER ligand binding domain mutations, Y537S and D538G. We found that these mutations induce differential expression of thousands of genes, the majority of which are specific to one or the other mutation and are not observed upon estrogen treatment of wildtype cells. The mutant-specific genes show consistent differential expression across ER mutant lines developed in other laboratories. The observed gene expression changes cannot be explained by constitutive ER activity alone, as wildtype cells with long term estrogen exposure only exhibit some of these transcriptional changes, suggesting that mutant ER causes novel regulatory effects that are not simply due to constant activity. While ER mutations have minor effects on ER genomic binding, with the exception of ligand independence, we observed substantial differences in chromatin accessibility due to ER mutations. Mutant ER is bound to approximately a quarter of mutant-enriched accessible regions that are enriched for other DNA binding factors including FOXA1, CTCF, and OCT1. Our findings indicate that mutant ER causes several consistent effects on gene expression both indirectly and through constant activity.
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Project description:How breast cancers respond to endocrine therapy strongly depends on the expression of the estrogen and progesterone receptors (ER and PR, respectively), with doublenegative ER-/PR- breast cancers having worse clinical outcome than ER+/PR+ breast cancers. Although much is known about ERα gene (ESR1) regulation after hormonal stimulation, how it is regulated in the absence of hormones is not fully understood. We used ER+/PR+ positive breast cancer cells to investigate the role of PR in ESR1 gene regulation in the absence of hormones. We show that PR binds to the low-methylated ESR1 promoter and maintains both gene expression and the DNA methylation profile of the ESR1 locus in hormone-deprived breast cancer cells. Depletion of PR reduces ESR1 expression, with a concomitant increase in gene promoter methylation. The high amount of DNA methylation in the ESR1 promoter of PR-depleted cells persists after the stable re-expression of PR and inhibits PR binding to this genomic region. Consequently, the rescue of PR expression in PR-depleted cells is insufficient to restore ESR1 expression. Consistent with these data, DNA methylation impedes PR binding to consensus progesterone responsive elements in vitro. These findings help us understand the complex crosstalk between PR and ER, and suggest that the analysis of DNA methylation of ESR1 promoter in breast cancer cells can help to design the appropriate targeted therapies for different types of breast cancer patients.
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