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dc.contributor.authorO'Driscoll, Lorraineen
dc.date.accessioned2014-10-14T15:50:06Z
dc.date.available2014-10-14T15:50:06Z
dc.date.issued2014en
dc.date.submitted2014en
dc.identifier.citationCorcoran C, Rani S, Breslin S, Gogarty M, Ghobrial IM, Crown J, O'Driscoll L, miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer, Mol. Cancer, 13, 2014, 71 - 79en
dc.identifier.otherYen
dc.identifier.urihttp://hdl.handle.net/2262/71515
dc.descriptionPUBLISHEDen
dc.description.abstractBACKGROUND: While the treatment of HER2 over-expressing breast cancer with recent HER-targeted drugs has been highly effective for some patients, primary (also known as innate) or acquired resistance limits the success of these drugs. microRNAs have potential as diagnostic, prognostic and predictive biomarkers, as well as replacement therapies. Here we investigated the role of microRNA-630 (miR-630) in breast cancer progression and as a predictive biomarker for response to HER-targeting drugs, ultimately yielding potential as a therapeutic approach to add value to these drugs. METHODS: We investigated the levels of intra- and extracellular miR-630 in cells and conditioned media from breast cancer cell lines with either innate- or acquired- resistance to HER-targeting lapatinib and neratinib, compared to their corresponding drug sensitive cell lines, using qPCR. To support the role of miR-630 in breast cancer, we examined the clinical relevance of this miRNA in breast cancer tumours versus matched peritumours. Transfection of miR-630 mimics and inhibitors was used to manipulate the expression of miR-630 to assess effects on response to HER-targeting drugs (lapatinib, neratinib and afatinib). Other phenotypic changes associated with cellular aggressiveness were evaluated by motility, invasion and anoikis assays. TargetScan prediction software, qPCR, immunoblotting and ELISAs, were used to assess miR-630's regulation of mRNA, proteins and their phosphorylated forms. RESULTS: We established that introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism which we have determined to, at least partly, involve miR-630's regulation of IGF1R. Conversely, we demonstrated that blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby introducing miR-630 into cells reduced cellular aggression while inhibition of miR-630 induced a more aggressive cellular phenotype. CONCLUSIONS: Taken together, our findings suggest miR-630 as a key regulator of cancer cell progression in HER2 over-expressing breast cancer, through targeting of IGF1R. This study supports miR-630 as a diagnostic and a predictive biomarker for response to HER-targeted drugs and indicates that the therapeutic addition of miR-630 may enhance and improve patients' response to HER-targeting drugs.en
dc.format.extent71en
dc.format.extent79en
dc.language.isoenen
dc.relation.ispartofseriesMol. Canceren
dc.relation.ispartofseries13en
dc.rightsYen
dc.subjectPharmaceutical Scienceen
dc.titlemiR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast canceren
dc.typeJournal Articleen
dc.contributor.sponsorScience Foundation Ireland (SFI)en
dc.contributor.sponsorHealth Research Board (HRB)en
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/lodriscen
dc.identifier.rssinternalid92880en
dc.identifier.doi10.1186/1476-4598-13-71en
dc.rights.ecaccessrightsopenAccess
dc.contributor.sponsorGrantNumber08/SRC/B141en
dc.subject.TCDThemeCanceren
dc.subject.TCDTagBREAST CANCERen
dc.identifier.rssurihttp://www.ncbi.nlm.nih.gov/pubmed/24655723en
dc.identifier.orcid_id0000-0002-9860-8262en


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