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dc.contributor.authorWard, A.en_US
dc.contributor.authorShukla, K.en_US
dc.contributor.authorBalwierz, A.en_US
dc.contributor.authorSoons, Z.en_US
dc.contributor.authorKönig, R.en_US
dc.contributor.authorSahin, O.en_US
dc.contributor.authorWiemann, S.en_US
dc.date.accessioned2016-02-08T11:00:04Z
dc.date.available2016-02-08T11:00:04Z
dc.date.issued2014en_US
dc.identifier.issn0022-3417
dc.identifier.urihttp://hdl.handle.net/11693/26456
dc.description.abstractTamoxifen is an endocrine therapy which is administered to up to 70% of all breast cancer patients with oestrogen receptor alpha (ERα) expression. Despite the initial response, most patients eventually acquire resistance to the drug. MicroRNAs (miRNAs) are a class of small non-coding RNAs which have the ability to post-transcriptionally regulate genes. Although the role of a few miRNAs has been described in tamoxifen resistance at the single gene/target level, little is known about how concerted actions of miRNAs targeting biological networks contribute to resistance. Here we identified the miRNA cluster, C19MC, which harbours around 50 mature miRNAs, to be up-regulated in resistant cells, with miRNA-519a being the most highly up-regulated. We could demonstrate that miRNA-519a regulates tamoxifen resistance using gain- and loss-of-function testing. By combining functional enrichment analysis and prediction algorithms, we identified three central tumour-suppressor genes (TSGs) in PI3K signalling and the cell cycle network as direct target genes of miR-519a. Combined expression of these target genes correlated with disease-specific survival in a cohort of tamoxifen-treated patients. We identified miRNA-519a as a novel oncomir in ER+ breast cancer cells as it increased cell viability and cell cycle progression as well as resistance to tamoxifen-induced apoptosis. Finally, we could show that elevated miRNA-519a levels were inversely correlated with the target genes' expression and that higher expression of this miRNA correlated with poorer survival in ER+ breast cancer patients. Hence we have identified miRNA-519a as a novel oncomir, co-regulating a network of TSGs in breast cancer and conferring resistance to tamoxifen. Using inhibitors of such miRNAs may serve as a novel therapeutic approach to combat resistance to therapy as well as proliferation and evasion of apoptosis in breast cancer.en_US
dc.language.isoEnglishen_US
dc.source.titleJournal of Pathologyen_US
dc.relation.isversionofhttp://dx.doi.org/10.1002/path.4363en_US
dc.subjectBreast canceren_US
dc.subjectC19MC clusteren_US
dc.subjectCell cycle networken_US
dc.subjectMicroRNAsen_US
dc.subjectTamoxifen resistanceen_US
dc.subjectEstrogen receptor alphaen_US
dc.subjectMicroRNAen_US
dc.subjectMicrorna 519aen_US
dc.subjectPhosphatidylinositol 3 kinaseen_US
dc.subjectSmall untranslated RNAen_US
dc.subjectTamoxifenen_US
dc.subjectUnclassified drugen_US
dc.subjectAlgorithmen_US
dc.subjectApoptosisen_US
dc.subjectArticleen_US
dc.subjectBreast canceren_US
dc.subjectCell cycle progressionen_US
dc.subjectCell viabilityen_US
dc.subjectControlled studyen_US
dc.subjectCorrelation analysisen_US
dc.subjectDisease specific survivalen_US
dc.subjectEstrogen receptor positive breast canceren_US
dc.subjectGain of function mutationen_US
dc.subjectGene controlen_US
dc.subjectGene expressionen_US
dc.subjectGene targetingen_US
dc.subjectHumanen_US
dc.subjectHuman cellen_US
dc.subjectLoss of function mutationen_US
dc.subjectNucleotide sequenceen_US
dc.subjectPriority journalen_US
dc.subjectTumor suppressor geneen_US
dc.subjectBreast canceren_US
dc.subjectC19MC clusteren_US
dc.subjectCell cycle networken_US
dc.subjectMicroRNAsen_US
dc.subjectTamoxifen resistanceen_US
dc.subjectAntineoplastic Agents, Hormonalen_US
dc.subjectApoptosisen_US
dc.subjectBreast Neoplasmsen_US
dc.subjectCell Cycleen_US
dc.subjectCell Line, Tumoren_US
dc.subjectDrug Resistance, Neoplasmen_US
dc.subjectEstrogen Receptor alphaen_US
dc.subjectFemaleen_US
dc.subjectGene Expression Regulation, Neoplasticen_US
dc.subjectGenes, Tumor Suppressoren_US
dc.subjectHumansen_US
dc.subjectMicroRNAsen_US
dc.subjectPharmacogeneticsen_US
dc.subjectPhosphatidylinositol 3-Kinasesen_US
dc.subjectSignal Transductionen_US
dc.subjectTamoxifenen_US
dc.subjectTumor Markers, Biologicalen_US
dc.titleMicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast canceren_US
dc.typeArticleen_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.citation.spage368en_US
dc.citation.epage379en_US
dc.citation.volumeNumber233en_US
dc.citation.issueNumber4en_US
dc.identifier.doi10.1002/path.4363en_US
dc.publisherJohn Wiley and Sons Ltden_US


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