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dc.contributor.authorOverman, Jeroenen
dc.contributor.authorFontaine, Franken
dc.contributor.authorMoustaqil, Mehdien
dc.contributor.authorMittal, Deepaken
dc.contributor.authorSierecki, Emmaen
dc.contributor.authorSacilotto, Nataliaen
dc.contributor.authorZuegg, Johannesen
dc.contributor.authorRobertson, Avril Aben
dc.contributor.authorHolmes, Kelly-Annen
dc.contributor.authorSalim, Angela Aen
dc.contributor.authorMamidyala, Sreemanen
dc.contributor.authorButler, Mark Sen
dc.contributor.authorRobinson, Ashley Sen
dc.contributor.authorLesieur, Emmanuelleen
dc.contributor.authorJohnston, Wayneen
dc.contributor.authorAlexandrov, Kirillen
dc.contributor.authorBlack, Brian Len
dc.contributor.authorHogan, Benjamin Men
dc.contributor.authorDe Val, Sarahen
dc.contributor.authorCapon, Robert Jen
dc.contributor.authorCarroll, Jasonen
dc.contributor.authorBailey, Timothy Len
dc.contributor.authorKoopman, Peteren
dc.contributor.authorJauch, Ralfen
dc.contributor.authorSmyth, Mark Jen
dc.contributor.authorCooper, Matthew Aen
dc.contributor.authorGambin, Yannen
dc.contributor.authorFrancois, Mathiasen
dc.date.accessioned2019-05-02T23:30:23Z
dc.date.available2019-05-02T23:30:23Z
dc.date.issued2017-01-31en
dc.identifier.issn2050-084X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/292243
dc.description.abstractPharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics.
dc.format.mediumElectronicen
dc.languageengen
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectBlood Vesselsen
dc.subjectAnimalsen
dc.subjectZebrafishen
dc.subjectMiceen
dc.subjectBreast Neoplasmsen
dc.subjectDisease Models, Animalen
dc.subjectZebrafish Proteinsen
dc.subjectAntineoplastic Agentsen
dc.subjectTreatment Outcomeen
dc.subjectProteomicsen
dc.subjectGenomicsen
dc.subjectTranscription, Geneticen
dc.subjectBiophysical Phenomenaen
dc.subjectSOXF Transcription Factorsen
dc.titlePharmacological targeting of the transcription factor SOX18 delays breast cancer in mice.en
dc.typeArticle
prism.publicationDate2017en
prism.publicationNameeLifeen
prism.volume6en
dc.identifier.doi10.17863/CAM.39392
dcterms.dateAccepted2016-12-07en
rioxxterms.versionofrecord10.7554/elife.21221en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-01-31en
dc.contributor.orcidSierecki, Emma [0000-0001-9970-868X]
dc.contributor.orcidZuegg, Johannes [0000-0001-6240-6020]
dc.contributor.orcidRobertson, Avril Ab [0000-0002-9652-8357]
dc.contributor.orcidSalim, Angela A [0000-0002-8177-5689]
dc.contributor.orcidBlack, Brian L [0000-0002-6664-8913]
dc.contributor.orcidHogan, Benjamin M [0000-0002-0651-7065]
dc.contributor.orcidCapon, Robert J [0000-0002-8341-7754]
dc.contributor.orcidCarroll, Jason [0000-0003-3643-0080]
dc.contributor.orcidKoopman, Peter [0000-0001-6939-0914]
dc.contributor.orcidJauch, Ralf [0000-0002-6590-9579]
dc.contributor.orcidGambin, Yann [0000-0001-7378-8976]
dc.contributor.orcidFrancois, Mathias [0000-0002-9846-6882]
dc.identifier.eissn2050-084X
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (C14303_do not transfer)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International