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dc.contributor.authorHruschka, Natascha
dc.contributor.authorKalisz, Mark
dc.contributor.authorSubijana, Maria
dc.contributor.authorGraña-Castro, Osvaldo
dc.contributor.authorDel Cano-Ochoa, Francisco
dc.contributor.authorBrunet, Laia Paré
dc.contributor.authorChernukhin, Igor
dc.contributor.authorSagrera, Ana
dc.contributor.authorDe Reynies, Aurelien
dc.contributor.authorKloesch, Bernhard
dc.contributor.authorChin, Suet-Feung
dc.contributor.authorBurgués, Octavio
dc.contributor.authorAndreu, David
dc.contributor.authorBermejo, Begoña
dc.contributor.authorCejalvo, Juan Miguel
dc.contributor.authorSutton, Joe
dc.contributor.authorCaldas, Carlos
dc.contributor.authorRamón-Maiques, Santiago
dc.contributor.authorCarroll, Jason S.
dc.contributor.authorPrat, Aleix
dc.contributor.authorReal, Francisco X.
dc.contributor.authorMartinelli, Paola
dc.date.accessioned2020-08-27T15:08:45Z
dc.date.available2020-08-27T15:08:45Z
dc.date.issued2020-06-25
dc.date.submitted2020-03-24
dc.identifier.issn0950-9232
dc.identifier.others41388-020-1376-3
dc.identifier.other1376
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/309688
dc.descriptionFunder: Spanish Ministry of Science, Innovation, and University. BFU2016-80570-R
dc.descriptionFunder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289
dc.descriptionFunder: Fundación Científica Asociación Española Contra el Cáncer (Scientific Foundation, Spanish Association Against Cancer); doi: https://doi.org/10.13039/501100002704
dc.description.abstractAbstract: As the catalog of oncogenic driver mutations is expanding, it becomes clear that alterations in a given gene might have different functions and should not be lumped into one class. The transcription factor GATA3 is a paradigm of this. We investigated the functions of the most common GATA3 mutation (X308_Splice) and five additional mutations, which converge into a neoprotein that we called “neoGATA3,” associated with excellent prognosis in patients. Analysis of available molecular data from >3000 breast cancer patients revealed a dysregulation of the ER-dependent transcriptional response in tumors carrying neoGATA3-generating mutations. Mechanistic studies in vitro showed that neoGATA3 interferes with the transcriptional programs controlled by estrogen and progesterone receptors, without fully abrogating them. ChIP-Seq analysis indicated that ER binding is reduced in neoGATA3-expressing cells, especially at distal regions, suggesting that neoGATA3 interferes with the fine tuning of ER-dependent gene expression. This has opposite outputs in distinct hormonal context, having pro- or anti-proliferative effects, depending on the estrogen/progesterone ratio. Our data call for functional analyses of putative cancer drivers to guide clinical application.
dc.languageen
dc.publisherNature Publishing Group UK
dc.subjectArticle
dc.subject/631/67/1347
dc.subject/631/67/68
dc.subject/13/1
dc.subject/13/51
dc.subject/38/39
dc.subject/82/80
dc.subject/96/106
dc.subject/45/22
dc.subject/45/90
dc.subjectarticle
dc.titleThe GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver
dc.typeArticle
dc.date.updated2020-08-27T15:08:44Z
prism.endingPage5467
prism.issueIdentifier32
prism.publicationNameOncogene
prism.startingPage5455
prism.volume39
dc.identifier.doi10.17863/CAM.56782
dcterms.dateAccepted2020-06-16
rioxxterms.versionofrecord10.1038/s41388-020-1376-3
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidKalisz, Mark [0000-0002-8770-2798]
dc.contributor.orcidDel Cano-Ochoa, Francisco [0000-0003-3093-3103]
dc.contributor.orcidAndreu, David [0000-0002-6317-6666]
dc.contributor.orcidCaldas, Carlos [0000-0003-3547-1489]
dc.contributor.orcidRamón-Maiques, Santiago [0000-0001-9674-8088]
dc.contributor.orcidCarroll, Jason S. [0000-0003-3643-0080]
dc.contributor.orcidPrat, Aleix [0000-0003-2377-540X]
dc.contributor.orcidReal, Francisco X. [0000-0001-9501-498X]
dc.contributor.orcidMartinelli, Paola [0000-0002-1643-8731]
dc.identifier.eissn1476-5594
pubs.funder-project-idAustrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung) (P27361-B23, P27361-B23, P27361-B23)
pubs.funder-project-idMinistry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación) (SAF2011-29530, SAF2011-29530, SAF2015-70553-R)


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