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ETV4 is necessary for estrogen signaling and growth in endometrial cancer cells [ChIP-seq]

ABSTRACT: Estrogen signaling through estrogen receptor alpha (ER) plays a major role in endometrial cancer risk and progression; however, the molecular mechanisms underlying ER’s regulatory role in endometrial cancer are poorly understood. In breast cancer cells, ER genomic binding is enabled by FOXA1 and GATA3, but the transcription factors that control ER genomic binding in endometrial cancer cells remain unknown. We previously identified ETV4 as a candidate factor controlling ER genomic binding in endometrial cancer cells and here we explore the functional importance of ETV4. Homozygous deletion of ETV4, using CRISPR/Cas9, led to greatly reduced ER binding at the majority of loci normally bound by ER. Consistent with the dramatic loss of ER binding, the gene expression response to estradiol was dampened for most genes. ETV4 contributes to estrogen signaling in two distinct ways; ETV4 loss impacts chromatin accessibility at some ER bound loci and impairs ER nuclear translocation. The diminished estrogen signaling upon ETV4 deletion led to decreased growth, particularly in 3D culture where hollow organoids were formed. Our results show that ETV4 plays a necessary role in estrogen signaling in endometrial cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE129803 | GEO | 2019/04/23

REPOSITORIES: GEO

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ETV4 is necessary for estrogen signaling and growth in endometrial cancer cells [RNA-seq]

Project description:Estrogen signaling through estrogen receptor alpha (ER) plays a major role in endometrial cancer risk and progression; however, the molecular mechanisms underlying ER’s regulatory role in endometrial cancer are poorly understood. In breast cancer cells, ER genomic binding is enabled by FOXA1 and GATA3, but the transcription factors that control ER genomic binding in endometrial cancer cells remain unknown. We previously identified ETV4 as a candidate factor controlling ER genomic binding in endometrial cancer cells and here we explore the functional importance of ETV4. Homozygous deletion of ETV4, using CRISPR/Cas9, led to greatly reduced ER binding at the majority of loci normally bound by ER. Consistent with the dramatic loss of ER binding, the gene expression response to estradiol was dampened for most genes. ETV4 contributes to estrogen signaling in two distinct ways; ETV4 loss impacts chromatin accessibility at some ER bound loci and impairs ER nuclear translocation. The diminished estrogen signaling upon ETV4 deletion led to decreased growth, particularly in 3D culture where hollow organoids were formed. Our results show that ETV4 plays a necessary role in estrogen signaling in endometrial cancer cells.

2019-04-23 | GSE129804 | GEO

ETV4 is necessary for estrogen signaling and growth in endometrial cancer cells [ATAC-seq]

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Estrogen receptor alpha mutations in breast cancer cells cause gene expression changes through constant activity and through secondary effects [ATAC-seq]

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 | GSE148278 | GEO

Estrogen receptor alpha mutations in breast cancer cells cause gene expression changes through constant activity and through secondary effects [ChIP-seq]

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2020-04-08 | GSE148276 | GEO

Clinical and genomic crosstalk between glucocorticoid receptor and estrogen receptor α in endometrial cancer [RNA-seq]

Project description:Steroid hormone receptors are simultaneously active in many tissues and capable of altering each other's function. Estrogen receptor ɑ (ER) and glucocorticoid receptor (GR) are expressed in the uterus and their ligands have opposing effects on uterine growth. In endometrial tumors expressing high levels of ER, we surprisingly found that expression of GR is associated with poor prognosis. Dexamethasone reduced normal uterine growth in vivo; however, this growth inhibition was abolished in estrogen-induced endometrial hyperplasia. We observed low genomic binding site overlap when ER and GR are induced with their respective ligands; however, upon simultaneous induction they co-occupy more sites. GR binding is significantly altered by estradiol with GR recruited to ER bound loci that become more accessible upon estradiol induction. Gene expression responses to co-treatment were more similar to estradiol, but with novel regulated genes. Our results suggest phenotypic and molecular interplay between ER and GR in endometrial cancer.

2018-03-13 | GSE109892 | GEO

Clinical and genomic crosstalk between glucocorticoid receptor and estrogen receptor α in endometrial cancer [ChIP-seq]

2018-03-13 | GSE109891 | GEO

Clinical and genomic crosstalk between glucocorticoid receptor and estrogen receptor α in endometrial cancer [ATAC-seq]

2018-03-13 | GSE109890 | GEO

ETV4 is necessary for estrogen signaling and growth in endometrial cancer cells

Project description:ETV4 is necessary for estrogen signaling and growth in endometrial cancer cells

| PRJNA532873 | ENA

Allele-specific gene regulation, phenotypes, and therapeutic vulnerabilities in estrogen receptor alpha mutant endometrial cancer (xenograft RNA-seq)

Project description:Activating estrogen receptor alpha (ER) mutations are present in primary endometrial and metastatic breast cancers, promoting estrogen-independent activation of the receptor. Functional characterizations in breast cancer have established unique molecular and phenotypic consequences of the receptor, yet the impact of ER mutations in endometrial cancer has not been fully explored. In this study, we used CRISPR-Cas9 to model the clinically prevalent ER-Y537S mutation and compared results to ER-D538G to discover allele-specific differences between ER mutations in endometrial cancer. We found that constitutive activity of mutant ER resulted in changes in the expression of thousands of genes, stemming from combined alterations to ER binding and chromatin accessibility. The unique gene expression programs resulted in ER mutant cells developing increased cancer associated phenotypes, including migration, invasion, anchorage independent growth, and growth in vivo. To uncover potential treatment strategies, we identified ER associated proteins via Rapid Immunoprecipitation and Mass Spectrometry of Endogenous Proteins (RIME) and interrogated two candidates, CDK9 and NCOA3. Inhibition of these regulatory protein resulted in decreased growth and migration, representing potential novel treatment strategies for ER mutant endometrial cancer. Taken together, this study provides insight into ER mutant activity in endometrial cancer and identifies potential therapies for women with ER mutant endometrial cancer.

2023-05-06 | GSE231744 | GEO

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