Hruschka, NataschaKalisz, MarkSubijana, MariaGraña-Castro, OsvaldoDel Cano-Ochoa, FranciscoBrunet, Laia ParéChernukhin, IgorSagrera, AnaDe Reynies, AurelienKloesch, BernhardChin, Suet-FeungBurgués, OctavioAndreu, DavidBermejo, BegoñaCejalvo, Juan MiguelSutton, JoeCaldas, CarlosRamón-Maiques, SantiagoCarroll, Jason SPrat, AleixReal Arribas, FranciscoMartinelli, Paola2024-02-132024-02-132020-08Oncogene . 2020;39(32):5455-5467.http://hdl.handle.net/20.500.12105/18189As 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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Breast NeoplasmsCell CycleFemaleGATA3 Transcription FactorHumansMutationOncogenesRNA SplicingRNA, MessengerReceptors, EstrogenReceptors, ProgesteroneT-LymphocytesAttribution-NonCommercial-NoDerivatives 4.0 Internacional325873993932545510.1038/s41388-020-1376-31476-5594Oncogenehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410826/open access