Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Estrogen-independent molecular actions of mutant estrogen receptor alpha in endometrial cancer [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE132428 | GEO | 2019/06/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Estrogen-independent molecular actions of mutant estrogen receptor alpha in endometrial cancer [ChIP-seq]

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.

2019-06-11 | GSE132426 | GEO

Estrogen-independent molecular actions of mutant estrogen receptor alpha in endometrial cancer [ATAC-seq]

2019-06-11 | GSE132424 | GEO

ESR1 Y537S and D538G mutations drive resistance to CDK4/6 inhibitors in estrogen receptor-positive breast cancer

Project description:Purpose: Breast cancers with ESR1 mutations are resistant to antiestrogen therapy. We aimed to investigate the association of ESR1 mutations with resistance to CDK4/6 inhibitors (CDK4/6i) using real-world data analysis and experimental validation. Patients and Methods: A total of 3,958 patients with estrogen receptor-positive (ER+) metastatic breast cancer with DNA sequencing data were analyzed. Breast tumor DNA and circulating tumor (ct) DNA were sequenced using the Tempus xT tumor assay and Tempus xF liquid biopsy, respectively. Patients were stratified into either treated with CDK4/6i (breast tumors: 1,070; ctDNA: 1,885) or CDK4/6i naïve (breast tumors: 750; ctDNA: 253). Engineered MCF7 cells carrying ESR1 Y537S or D538G knock-in mutations were used to study antitumor efficacy of the CDK4/6i, palbociclib in vitro and in vivo. Results: In both xF and xT assays, ESR1 mutations were the only somatic alterations significantly more frequent in those who received CDK4/6i than those who did not. Knock-in of ESR1 Y537S or ESR1 D538G in MCF7 cells resulted in upregulation of cell cycle-related gene signatures upon treatment with CDK4/6i ± antiestrogen compared to cells with non-mutant ESR1. MCF7 xenografts harboring ESR1 Y537S and D538G mutations established in nude mice were resistant to palbociclib. Conclusions: We report herein real-world and preclinical evidence that ESR1 mutations, particularly Y537S and D538G, can drive resistance to CDK4/6 inhibitors.

2024-11-12 | GSE281302 | GEO

CRISPR-Cas9 directed modelling of estrogen receptor mutations identified in breast cancer

Project description:Estrogen receptor (ER) is the major driver of a large proportion of breast cancers, and many therapies have been designed to target it. These include anti-estrogens, which target ER directly, and aromatase inhibitors, which instead prevent the biosynthesis of estrogen in post-menopausal women. These therapies have been largely successful, but unfortunately many patients eventually succumb to resistance. A hotspot of mutations in exon 8 of ESR1, which cause the ER to be constitutively active, have been discovered in advanced breast cancer patients, and are one cause of resistance to aromatase inhibitors as well as a reduced response to anti-estrogen therapies. Since most studies in to these mutations have so far focused on the mostly commonly seen mutations, Y537S and D538G, it is important to extend our understanding to other frequently found mutations to determine whether there are intrinsic differences between them. For this purpose, CRISPR-Cas9 was used in order to model the following mutations found in exon 8 of ESR1 in breast cancer patients, L536R, Y537C, Y537S, Y537N and D538G, in MCF7 cells, with between two to four clones of each mutation generated. Growth in the absence of estrogen and in the presence of various SERDs was tested to investigate differences in sensitivity between mutations. RNA-seq was carried out in the ESR1 mutant MCF7 lines under full medium conditions to look for gene expression changes compared to WT, shared between all mutations, or the possibility of differences between specific mutations, which were not due to the fact that the ESR1 mutant lines can grow in the absence of estrogen. The results of which should provide great insight into potential alternative genes or pathways, which could be targeted in patients harbouring these mutations.

2022-08-09 | GSE147745 | GEO

Allele-specific gene regulation, phenotypes, and therapeutic vulnerabilities in estrogen receptor alpha mutant endometrial cancer (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.

2022-06-17 | GSE205878 | GEO

Allele-specific gene regulation, phenotypes, and therapeutic vulnerabilities in estrogen receptor alpha mutant endometrial cancer (ChIP-Seq)

2022-06-17 | GSE205877 | GEO

Allele-specific gene regulation, phenotypes, and therapeutic vulnerabilities in estrogen receptor alpha mutant endometrial cancer (ATAC-Seq)

2022-06-17 | GSE205875 | GEO

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

2023-05-06 | GSE231744 | GEO

Targeting ESR1 mutation-induced transcriptional addiction with BET inhibition

Project description:We investigated the therapeutic potential of BET inhibition to target ESR1 mutation-induced “transcriptional addiction” in ER-positive breast cancer. Our studies show that ESR1 mutant (Y537S and D538G) cells activate unique transcriptional programs that are targeted by OTX015, a BET inhibitor

2022-06-18 | GSE206185 | GEO

ESR1 Y537S and D538G mutations drive resistance to CDK4/6 inhibitors in estrogen receptor-positive breast cancer

Project description:ESR1 Y537S and D538G mutations drive resistance to CDK4/6 inhibitors in estrogen receptor-positive breast cancer

| PRJNA1183347 | ENA