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Título: | The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver |
Autor: | Hruschka, Natascha; Kalisz, Mark; Subijana, María; Graña-Castro, Osvaldo; Caño-Ochoa, Francisco del CSIC ORCID; Paré Brunet, Laia; Sagrera, Ana; Reynies, Aurelien De; Kloesh, Bernhard; Chin, Suet-Feung; Burgués, Octavio; Andreu, David; Bermejo, Begoña; Cejalvo, Juan Miguel; Sutton, Joe; Caldas, Carlos; Ramón-Maiques, Santiago CSIC ORCID ; Carroll, Jason S.; Prat, Aleix; Real, Francisco X.; Martinelli, Paola | Fecha de publicación: | 25-jun-2020 | Citación: | Oncogene 39: 5455- 5467 (2020) | Resumen: | 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. | Versión del editor: | http://dx.doi.org/10.1038/s41388-020-1376-3 | URI: | http://hdl.handle.net/10261/220986 | DOI: | 10.1038/s41388-020-1376-3 | Identificadores: | doi: 10.1038/s41388-020-1376-3 issn: 1476-5594 |
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RamónMaiquesS_The GATA3 X308_Splice.pdf | 4,42 MB | Adobe PDF | Visualizar/Abrir |
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