Genomics

Dataset Information

341

Modeling the ESR1 tyrosine 537 mutation with CRISPR-Cas9 for mechanistic studies and evaluation of therapeutic approaches for metastatic breast cancer [ChIP-Seq]


ABSTRACT: Estrogen receptor-α (ERα) is an important driver of breast cancer and is the target for hormonal therapies, anti-estrogens and drugs that limit estrogen biosynthesis (aromatase inhibitors). Mutations in the ESR1 gene identified in metastatic breast cancer provide a potential mechanism for acquired resistance to hormone therapies. We have used CRISPR-Cas9 mediated genome editing in the MCF-7 breast cancer cell line, generating MCF-7-Y537S. MCF-7-Y537S cells encode a wild-type (tyrosine 537) and a mutant (serine 537) allele. Growth of the line is estrogen-independent and expression of ERα target genes is elevated in the absence of estrogen. ER ChIP-seq was carried out to map global ERα binding sites in the presence and absence of estrogen. RNA-seq following estrogen treatment was used for gene expression analysis. We show that expression of ER target genes and ER recruitment to ER binding regions is similar in MCF-7 and MCF-7-Y537S cells, except that ER recruitment to DNA and expression of ER target genes is frequently elevated in the absence of estrogen Hormone depleted MCF-7 LUC /Y537S mutant cells were treated with estrogen (10nM) or ETOH as vehicle control for 45 mins. Erα Chip-seq was performed using Illumnia methodology

ORGANISM(S): Homo sapiens  

SUBMITTER: Simak Ali   Alison Harrod  Van Thuy Mai Nguyen  Van T Nguyen  Luca Magnani 

PROVIDER: E-GEOD-78284 | ArrayExpress | 2016-10-25

SECONDARY ACCESSION(S): SRP070778GSE78284PRJNA313092

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications

Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer.

Harrod A A   Fulton J J   Nguyen V T M VTM   Periyasamy M M   Ramos-Garcia L L   Lai C-F CF   Metodieva G G   de Giorgio A A   Williams R L RL   Santos D B DB   Gomez P J PJ   Lin M-L ML   Metodiev M V MV   Stebbing J J   Castellano L L   Magnani L L   Coombes R C RC   Buluwela L L   Ali S S  

Oncogene 20161017 16


Drugs that inhibit estrogen receptor-α (ER) activity have been highly successful in treating and reducing breast cancer progression in ER-positive disease. However, resistance to these therapies presents a major clinical problem. Recent genetic studies have shown that mutations in the ER gene are found in >20% of tumours that progress on endocrine therapies. Remarkably, the great majority of these mutations localize to just a few amino acids within or near the critical helix 12 region of the ER  ...[more]

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