The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver

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  • dc.contributor.author Hruschka, Natascha
  • dc.contributor.author Andreu Martínez, David
  • dc.contributor.author Real, Francisco X.
  • dc.contributor.author Martinelli, Paola
  • dc.date.accessioned 2020-09-22T06:13:29Z
  • dc.date.available 2020-09-22T06:13:29Z
  • dc.date.issued 2020
  • dc.description.abstract 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.description.sponsorship Work in the lab of PM was supported by the Institute of Cancer Research of the Medical University Vienna and by the grant P27361-B23 from the Austrian Science Grant (FWF), FXR was supported by SAF2011-29530 and SAF2015-70553-R grants from Ministerio de Economía y Competitividad (Madrid, Spain) (co-funded by the ERDF-EU), Fundación Científica de la Asociación Española Contra el Cáncer. CNIO is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa SEV-2015-0510. Work in the lab of JSC and CC was supported by Cancer Research UK. Work in the lab of SRM was supported by the Spanish Ministry of Science, Innovation and Universities (BFU2016-80570-R; AEI/FEDER, UE).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Hruschka N, Kalisz M, Subijana M, Graña-Castro O, Del Cano-Ochoa F, Brunet LP et al. The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver. Oncogene. 2020; 39(32):5455-67. DOI: 10.1038/s41388-020-1376-3
  • dc.identifier.doi http://dx.doi.org/10.1038/s41388-020-1376-3
  • dc.identifier.issn 0950-9232
  • dc.identifier.uri http://hdl.handle.net/10230/45320
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Oncogene. 2020; 39(32):5455-67
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2011-29530
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-70553-R
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-80570-R
  • dc.rights © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Breast cancer
  • dc.subject.keyword Cancer genetics
  • dc.title The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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