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dc.contributor.authorMohd Nafi, SN
dc.contributor.authorGenerali, D
dc.contributor.authorKramer-Marek, G
dc.contributor.authorGijsen, M
dc.contributor.authorStrina, C
dc.contributor.authorCappelletti, M
dc.contributor.authorAndreis, D
dc.contributor.authorHaider, S
dc.contributor.authorLi, J-L
dc.contributor.authorBridges, E
dc.contributor.authorCapala, J
dc.contributor.authorIoannis, R
dc.contributor.authorHarris, AL
dc.contributor.authorKong, A
dc.date.accessioned2016-08-09T14:58:50Z
dc.date.available2016-08-09T14:58:50Z
dc.date.issued2014-08-15
dc.identifier.issn1949-2553
dc.identifier.issn1949-2553
dc.identifier.urihttp://hdl.handle.net/10026.1/5251
dc.description.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.

dc.format.extent5934-5949
dc.format.mediumPrint
dc.languageen
dc.language.isoeng
dc.publisherImpact Journals, LLC
dc.subjectAnimals
dc.subjectAntineoplastic Agents
dc.subjectBreast Neoplasms
dc.subjectCell Line, Tumor
dc.subjectCell Nucleus
dc.subjectDrug Resistance, Neoplasm
dc.subjectFemale
dc.subjectHeterografts
dc.subjectHumans
dc.subjectMCF-7 Cells
dc.subjectMice
dc.subjectPrognosis
dc.subjectReceptor, ErbB-2
dc.subjectReceptor, ErbB-4
dc.subjectTrastuzumab
dc.titleNuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer
dc.typejournal-article
dc.typeJournal Article
dc.typeResearch Support, N.I.H., Extramural
dc.typeResearch Support, Non-U.S. Gov't
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/25153719
plymouth.issue15
plymouth.volume5
plymouth.publisher-urlhttp://dx.doi.org/10.18632/oncotarget.1904
plymouth.publication-statusPublished
plymouth.journalOncotarget
dc.identifier.doi10.18632/oncotarget.1904
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine/UoA01 Clinical Medicine
dc.publisher.placeUnited States
dc.identifier.eissn1949-2553
dc.rights.embargoperiodNot known
rioxxterms.versionofrecord10.18632/oncotarget.1904
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review


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