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dc.contributor.authorAshenden, Men_US
dc.contributor.authorvan Weverwijk, Aen_US
dc.contributor.authorMurugaesu, Nen_US
dc.contributor.authorFearns, Aen_US
dc.contributor.authorCampbell, Jen_US
dc.contributor.authorGao, Qen_US
dc.contributor.authorIravani, Men_US
dc.contributor.authorIsacke, CMen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2017-05-26T15:42:09Z
dc.date.issued2017-09en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/28611109en_US
dc.identifier1535-7163.MCT-16-0731en_US
dc.identifier.citationMol Cancer Ther, 2017, 16 (9), pp. 1967 - 1978en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/667
dc.identifier.eissn1538-8514en_US
dc.identifier.doi10.1158/1535-7163.MCT-16-0731en_US
dc.description.abstractChemotherapy remains the mainstay of treatment for advanced breast cancer; however, resistance is an inevitable event for the majority of patients with metastatic disease. Moreover, there is little information available to guide stratification of first-line chemotherapy, crucial given the common development of multidrug resistance. Here, we describe an in vivo screen to interrogate the response to anthracycline-based chemotherapy in a syngeneic metastatic breast cancer model and identify JNK signaling as a key modulator of chemotherapy response. Combining in vitro and in vivo functional analyses, we demonstrate that JNK inhibition both promotes tumor cell cytostasis and blocks activation of the proapoptotic protein Bax, thereby antagonizing chemotherapy-mediated cytotoxicity. To investigate the clinical relevance of this dual role of JNK signaling, we developed a proliferation-independent JNK activity signature and demonstrate high JNK activity to be enriched in triple-negative and basal-like breast cancer subtypes. Consistent with the dual role of JNK signaling in vitro, high-level JNK pathway activation in triple-negative breast cancers is associated both with poor patient outcome in the absence of chemotherapy treatment and, in neoadjuvant clinical studies, is predictive of enhanced chemotherapy response. These data highlight the potential of monitoring JNK activity as early biomarker of response to chemotherapy and emphasize the importance of rational treatment regimes, particularly when combining cytostatic and chemotherapeutic agents. Mol Cancer Ther; 16(9); 1967-78. ©2017 AACR.en_US
dc.format.extent1967 - 1978en_US
dc.languageengen_US
dc.language.isoengen_US
dc.subjectAnimalsen_US
dc.subjectAnthracyclinesen_US
dc.subjectAntineoplastic Agentsen_US
dc.subjectBreast Neoplasmsen_US
dc.subjectCell Line, Tumoren_US
dc.subjectChemotherapy, Adjuvanten_US
dc.subjectDisease Models, Animalen_US
dc.subjectDrug Resistance, Neoplasmen_US
dc.subjectEnzyme Activationen_US
dc.subjectFemaleen_US
dc.subjectHumansen_US
dc.subjectJNK Mitogen-Activated Protein Kinasesen_US
dc.subjectMAP Kinase Signaling Systemen_US
dc.subjectMiceen_US
dc.subjectNeoadjuvant Therapyen_US
dc.subjectPrognosisen_US
dc.subjectProtein Kinase Inhibitorsen_US
dc.subjectRNA, Small Interferingen_US
dc.subjectTriple Negative Breast Neoplasmsen_US
dc.titleAn In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer.en_US
dc.typeJournal Article
dcterms.dateAccepted2017-05-18en_US
rioxxterms.versionofrecord10.1158/1535-7163.MCT-16-0731en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2017-09en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfMol Cancer Theren_US
pubs.issue9en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Cell Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics
pubs.publication-statusPublisheden_US
pubs.volume16en_US
pubs.embargo.termsNot knownen_US
icr.researchteamMolecular Cell Biologyen_US
icr.researchteamTranslational Oncogenomicsen_US
dc.contributor.icrauthorIsacke, Clareen_US
dc.contributor.icrauthorAshenden, Matthewen_US
dc.contributor.icrauthorIravani, Marjanen_US
dc.contributor.icrauthorCampbell, Jamesen_US
dc.contributor.icrauthorGao, Qiongen_US
dc.contributor.icrauthorVan Weverwijk, Anthoniaen_US


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