Evidence map›Paper›PMID 25153719›Full record

ArticleOncotarget2014

Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer.

Siti Norasikin Mohd Nafi, Daniele Generali, Gabriela Kramer-Marek, Merel Gijsen, Carla Strina, Mariarosa Cappelletti, Daniele Andreis, Syed Haider, Ji-Liang Li, Esther Bridges and 4 more

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

Article in Oncotarget, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
35citing papers in PubMed, 1 pooled it
3.4field-weighted citation impact, top 6% 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

35 citing papers in PubMed, 1 synthesis or guideline pooled it, 64 citations in OpenAlex.

  1. Pooled it
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  12. PET and SPECT Imaging of the EGFR Family (RTK Class I) in Oncology.International journal of molecular sciences · 2021
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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

14 authors at 5 institutions in 3 countries.

Siti Norasikin Mohd NafiHuman Epidermal Growth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Daniele GeneraliU.O. Multidisciplinare di Patologia Mammaria, U.S Terapia Molecolare e Farmacogenomica, A.O. Instituti Ospitalieri di Cremona, Viale Concordia 1, Cremona, Italy.
Gabriela Kramer-MarekInstitute of Cancer Research, Division of Radiotherapy and Imaging, 15 Cotswold Road, Belmont, Sutton, Surrey, UK.
Merel GijsenHuman Epidermal Growth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Carla StrinaU.O. Multidisciplinare di Patologia Mammaria, U.S Terapia Molecolare e Farmacogenomica, A.O. Instituti Ospitalieri di Cremona, Viale Concordia 1, Cremona, Italy.
Mariarosa CappellettiU.O. Multidisciplinare di Patologia Mammaria, U.S Terapia Molecolare e Farmacogenomica, A.O. Instituti Ospitalieri di Cremona, Viale Concordia 1, Cremona, Italy.
Daniele AndreisU.O. Multidisciplinare di Patologia Mammaria, U.S Terapia Molecolare e Farmacogenomica, A.O. Instituti Ospitalieri di Cremona, Viale Concordia 1, Cremona, Italy.
Syed HaiderGrowth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Ji-Liang LiGrowth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Esther BridgesGrowth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Jacek CapalaNational Institutes of Health, Radiation Oncology Branch, Bethesda MD, US.
Roxanis IoannisDepartment of Cellular Pathology, Oxford University Hospitals and Oxford Biomedical Research Centre, Oxford, UK.
Adrian L HarrisGrowth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Anthony KongHuman Epidermal Growth Factor Group, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
University of Oxford · GBIstituti Ospitalieri di Cremona · ITJohn Radcliffe Hospital · GBInstitute of Cancer Research · GBNational Institutes of Health · US

Funding

Cancer Research UK
6 · The paper itself

Abstract

The role of HER4 in breast cancer is controversial and its role in relation to trastuzumab resistance remains unclear. We showed that trastuzumab treatment and its acquired resistance induced HER4 upregulation, cleavage and nuclear translocation. However, knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in HER2 positive breast cancer cells. Preventing HER4 cleavage by a γ-secretase inhibitor and inhibiting HER4 tyrosine kinase activity by neratinib decreased trastuzumab-induced HER4 nuclear translocation and enhanced trastuzumab response. There was also increased nuclear HER4 staining in the tumours from BT474 xenograft mice and human patients treated with trastuzumab. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in HER2 positive breast cancer. Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in HER2 positive breast cancer. Therefore, our study provides novel findings that HER4 activation, cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in HER2 positive breast cancer. Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in HER2 positive breast cancer.

Indexed as

AnimalsAntineoplastic AgentsBreast NeoplasmsCell Line, TumorCell NucleusDrug Resistance, NeoplasmErb-b2 Receptor Tyrosine KinasesFemaleHeterograftsHumansMCF-7 CellsMicePrognosisReceptor, ErbB-4TrastuzumabAntineoplastic AgentsERBB2 protein, humanErb-b2 Receptor Tyrosine KinasesERBB4 protein, humanReceptor, ErbB-4Trastuzumab

Identifiers

PMID25153719
PMCPMC4171603
OpenAlexW2169430911

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.