Evidence map›Paper›PMID 27748765›Full record

ArticleOncogene2017

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

A Harrod, J Fulton, V T M Nguyen, M Periyasamy, L Ramos-Garcia, C-F Lai, G Metodieva, A de Giorgio, R L Williams, D B Santos and 9 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Oncogene, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers.

0numbers the graph read from it
0cells of the map it votes in
111citing papers in PubMed
8.9field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

111 citing papers in PubMed, 174 citations in OpenAlex.

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  12. TRIM24 as a therapeutic target in endocrine treatment-resistant breast cancer.Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
  13. PARP-1 as a novel target in endocrine-resistant breast cancer.Journal of experimental & clinical cancer research : CR · 2025
    Article
  14. Article
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  16. Review
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51 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors at 2 institutions in 1 country.

A HarrodDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
J FultonDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
V T M NguyenDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
M PeriyasamyDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
L Ramos-GarciaDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
C-F LaiDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
G MetodievaSchool of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK.
A de GiorgioDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
R L WilliamsDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
D B SantosDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
P J GomezDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
M-L LinDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
M V MetodievSchool of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK.
J StebbingDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
L CastellanoDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.ORCID 0000-0002-3059-4829
L MagnaniDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.ORCID 0000-0002-7534-0785
R C CoombesDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
L BuluwelaDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
S AliDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.ORCID 0000-0002-1320-0816
Hammersmith Hospital · GBUniversity of Essex · GB

Funding

Cancer Research UK 12011Cancer Research UK 14549Cancer Research UK 18784Cancer Research UK C37/A18784
6 · The paper itself

Abstract

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 hormone binding domain, where they are likely to be single allele mutations. Understanding how these mutations impact on ER function is a prerequisite for identifying methods to treat breast cancer patients featuring such mutations. Towards this end, we used CRISPR-Cas9 genome editing to make a single allele knock-in of the most commonly mutated amino acid residue, tyrosine 537, in the estrogen-responsive MCF7 breast cancer cell line. Genomic analyses using RNA-seq and ER ChIP-seq demonstrated that the Y537S mutation promotes constitutive ER activity globally, resulting in estrogen-independent growth. MCF7-Y537S cells were resistant to the anti-estrogen tamoxifen and fulvestrant. Further, we show that the basal transcription factor TFIIH is constitutively recruited by ER-Y537S, resulting in ligand-independent phosphorylation of Serine 118 (Ser118) by the TFIIH kinase, cyclin-dependent kinase (CDK)7. The CDK7 inhibitor, THZ1 prevented Ser118 phosphorylation and inhibited growth of MCF7-Y537S cells. These studies confirm the functional importance of ER mutations in endocrine resistance, demonstrate the utility of knock-in mutational models for investigating alternative therapeutic approaches and highlight CDK7 inhibition as a potential therapy for endocrine-resistant breast cancer mediated by ER mutations.

Indexed as

Antineoplastic AgentsBreast NeoplasmsCell ProliferationCRISPR-Cas SystemsCyclin-Dependent Kinase-Activating KinaseCyclin-Dependent KinasesEstrogen AntagonistsEstrogen Receptor alphaEstrogensFemaleGene Knock-In TechniquesHistonesHumansMCF-7 CellsMutationPhosphorylationafimoxifeneAntineoplastic AgentsCDK7 protein, humanCyclin-Dependent Kinase-Activating KinaseCyclin-Dependent KinasesESR1 protein, humanEstrogen AntagonistsEstrogen Receptor alphaEstrogensHistonesSerineTamoxifen

Identifiers

PMID27748765
PMCPMC5245767
OpenAlexW2538138106

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.