T47D cell line transfected with various ESR1 fusion genes (or with estrogen treatment), vs. YFP transfection alone
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE69774 | GEO | 2015/06/12
SECONDARY ACCESSION(S): PRJNA286743
REPOSITORIES: GEO
Similar Datasets
Project description:Gene expression profiling of the downstream transcriptional changes induced by ESR1 fusion genes observed in human breast tumors resistant to hormone therapy Experimental T47D cells stably expressing ESR1 fusion genes (or T47D cells treated with estradiol) vs. T47D cells expressing YFP
2015-06-12 | E-GEOD-69774 | biostudies-arrayexpress
Project description:Transcriptionally active ESR1 fusions promote endocrine therapy (ET)-resistant growth and metastasis of estrogen receptor-alpha positive (ERα+) breast cancer. Currently, there are no targeted treatment options for tumors harboring active fusions because the ESR1 ligand binding domain (LBD) has been replaced with non-drug binding sequences from the 3’ partner gene. A mass spectrometry (MS)-based Kinase Inhibitor Pulldown Assay (KIPA) demonstrated an increase of multiple receptor tyrosine kinases including RET in T47D cells expressing active ESR1 fusions. Integrated proteogenomics defined tumor subsets that could be responsive to RET and CDK4/6 directed therapy from 22 biologically heterogeneous ERα+ patient-derived xenograft (PDX) tumors. Inhibition of RET by repurposing an FDA-approved drug significantly suppressed ESR1 fusion-driven growth of cell, PDX-derived organoid (PDXO) and PDX models. CDK4/6 inhibitor treatment showed similar tumor reductions to RET inhibition. Here, we reveal therapeutic kinase vulnerabilities in ESR1 fusion-driven tumors, which will lay the framework for future clinical trials.
2023-10-24 | PXD033339 | Pride
Project description:Estrogen receptor-α (ESR1) is an important transcriptional regulator in the mammalian oviduct, however ESR1-dependent regulation of this organ is not well defined, especially at the genomic level. The objective of this study was therefore to investigate estradiol- and ESR1-dependent regulation of the transcriptome of the oviduct using transgenic mice, both with (ESR1KO) and without (wild-type, WT) a global deletion of this transcription factor using the Affymetrix Genechip Mouse Genome 430-2.0 arrays.
2015-11-30 | GSE72614 | GEO
Project description:RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor positive (ER+) breast cancer but their role in disease pathogenesis remains unclear. Herein we examined multiple in-frame and out-of-frame ESR1 fusions and found that two, both identified in advanced endocrine treatment resistant disease, encoded stable and functional in-frame fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, the N-terminal, DNA binding and dimerization motifs encoded by exons 2-6 were fused to C terminal sequences from the partner gene. Functional properties included estrogen-independent growth, constitutive expression of ER target genes, anti-estrogen resistance, induction of cellular motility in vitro and the development of lung metastasis in vivo. Chromatin immunoprecipitation and RNA sequencing experiments showed both fusions uniquely activated a metastasis-associated transcriptional program. ESR1-e6>YAP1 and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, palbociclib, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective.
2018-07-11 | GSE116170 | GEO
Project description:In this study we show that depletion of the cohesin subunit SMC3 or the Mediator subunit MED12 significantly impairs the ERα-regulated transcriptome. Surprisingly, SMC3 depletion appears to elicit this effect indirectly by rapidly decreasing ESR1 transcription and ERα protein levels. Moreover, we provide evidence that both SMC3 and MED12 colocalize on the ESR1 gene and are mutually required for occupancy as well as for transcriptional elongation. Finally, we show that extended proteasome inhibition decreases the mRNA expression of cohesin subunits which accompanies a decrease in ESR1 mRNA and ERα protein levels as well as estrogen-regulated transcription. Conclusions: These results identify the ESR1 gene as a cohesin/Mediator-dependent gene and indicate that this regulation may potentially be exploited for the treatment of estrogen-dependent breast cancer. This set contains 18 microarray samples with triplicates for each condition. 3 control siRNA, 3 control estrogen stimulated, 3 siRNA Med12 knockdown, 3 siRNA Med12 knockdown estrogen stimulated, 3 siRNA Smc3 knockdown, 3 siRNA Smc3 knockdown estrogen stimulated.
2013-05-20 | E-GEOD-38252 | biostudies-arrayexpress
Project description:Purpose: Transcriptome analysis of ESR1 mutant cells was performed via sequencing total RNA in T47D and MCF7 cell lines containing Y537S and D538G mutations.
2017-06-03 | GSE89888 | GEO
Project description:In this study we show that depletion of the cohesin subunit SMC3 or the Mediator subunit MED12 significantly impairs the ERα-regulated transcriptome. Surprisingly, SMC3 depletion appears to elicit this effect indirectly by rapidly decreasing ESR1 transcription and ERα protein levels. Moreover, we provide evidence that both SMC3 and MED12 colocalize on the ESR1 gene and are mutually required for occupancy as well as for transcriptional elongation. Finally, we show that extended proteasome inhibition decreases the mRNA expression of cohesin subunits which accompanies a decrease in ESR1 mRNA and ERα protein levels as well as estrogen-regulated transcription. Conclusions: These results identify the ESR1 gene as a cohesin/Mediator-dependent gene and indicate that this regulation may potentially be exploited for the treatment of estrogen-dependent breast cancer.
2013-05-20 | GSE38252 | GEO
Project description:adt06-01_esr1-drn_dexamethasone - esr1-drn - Identification of the target genes of the ESR1/DRN TF using dexamethasone induction - Identification of the target genes of the ESR1/DRN TF using dexamethasone induction Keywords: normal vs transgenic comparison 5 dye-swap - CATMA arrays
2008-09-25 | E-GEOD-12919 | biostudies-arrayexpress
Project description:Uterine fibroids, benign tumors of the smooth muscle layer of the uterus, plague approximately 80% of the female population by age 50. While there have been efforts to understand the mechanism behind this pathophysiology, it largely remains unclear. Lack of preclinical animal models that recapitulate aberrant steroid hormone pathways in UL has significantly hampered the development of long-term hormonal therapies for uterine fibroids. In addition, cultured myometrial as well as leiomyoma smooth muscle cells rapidly silence both estrogen receptor alpha (ESR1) and progesterone receptor (PGR) expression through unknown mechanisms, further limiting in vitro mechanistic studies of UL. Previous work by our lab has determined the loss of REST, a master regulator of epigenetic gene silencing, in leiomyoma results in the upregulation of ESR1 targets and therefore estrogen signaling. Using ChIP-PCR, we find REST is directly associated with ESR1 genomic locus, playing a role in its epigenetic regulation. ChIP-seq analysis of Rest cKO mouse uterus samples reveal a global role for REST in the regulation of progesterone receptor target genes and highlights alterations in PGR binding within the Esr1 locus. Additionally, we find REST inhibition of ESR1 expression is regulated through upstream WNT planar cell polarity molecule, PRICKLE1. Based on REST’s role in silencing ESR1 expression in cultured myometrial cells, our results support the development of a potential cell culture method to maintain ESR1 expression through REST modulation. Finally, we establish a broad role for REST in epigenetic regulation relevant to leiomyoma pathophysiology.
2026-01-21 | GSE306878 | GEO
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