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Transcriptional profiling of estrogen receptor fusion genes in breast cancer cell lines

ABSTRACT: Transcriptional profiling of estrogen receptor fusion genes in breast cancer cell lines

PROVIDER: PRJNA789898 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17263744_1.fastq.gz	Fastqsanger.gz
	SRR17263744_2.fastq.gz	Fastqsanger.gz
	SRR17263745_1.fastq.gz	Fastqsanger.gz
	SRR17263745_2.fastq.gz	Fastqsanger.gz
	SRR17263746_1.fastq.gz	Fastqsanger.gz

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Transcriptional properties of estrogen receptor fusion genes.

Project description:Transcriptional properties of estrogen receptor fusion genes.

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Transcriptional properties of estrogen receptor fusion genes.

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.

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RNA sequencing to identify fusion transcripts in late-stage relapse patients with estrogen receptor positive breast cancer

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Transcriptional profiling of estrogen receptor fusion genes in breast cancer cell lines

Project description:Genomic analysis has recently identified multiple ESR1 gene translocations in estrogen receptor-alpha positive (ERα+) metastatic breast cancer (MBC) that encode chimeric proteins whereby the ESR1 ligand binding domain (LBD) is replaced by C-terminal sequences from many different gene partners. Here we functionally screened 15 ESR1 fusions and identified 10 that promoted estradiol-independent cell growth, motility, invasion, EMT and resistance to fulvestrant. RNA sequencing identified a gene expression pattern specific to functionally active ESR1 gene fusions that was subsequently reduced to a diagnostic 24-gene signature. This signature was further examined in 20 ERα+ patient-derived xenografts (PDXs) and in 55 ERα+ MBC samples. The 24-gene signature successfully identified cases harboring ESR1 gene fusions and also accurately diagnosed the presence of activating ESR1 LBD point mutations. Therefore, the 24-gene signature represents an efficient approach to screening samples for the presence of diverse somaticESR1 mutations and translocations that drive endocrine treatment failure in MBC.

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Project description:Hyperactivation of phosphatidylinositol-3 kinase (PI3K) promotes escape from hormone dependence in estrogen receptor-positive breast cancer. A significant fraction of breast cancers exhibit de novo or acquired resistance to estrogen deprivation. We used gene expression microarrays to identify genes and pathways that are commonly dysregulated in ER+ cell lines with acquired hormone-independent growth. MCF-7, ZR75-1, MDA-361, and HCC-1428 ER+, estrogen-responsive breast cancer cells were cultured under hormone-depleted conditions (10% DCC-FBS) for several months until sustainable hormone-independent cell populations emerged. Parental and long-term estrogen-deprived (LTED) cells were treated with 10% dextran-coated charcoal-treated fetal bovine serum (DCC-FBS) x 24 hrs prior to RNA harvest for array analysis.

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Project description:The aim of presented study was to assess the relationship between the presence of estrogen receptor and WWOX gene in breast cancer cell lines.

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Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer

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Comparison between Estrogen receptor positive and Estrogen receptor negative breast cancer samples

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