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

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Hruschka, Natascha 
Subijana, Maria 
Graña-Castro, Osvaldo 
Del Cano-Ochoa, Francisco  ORCID logo


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.


Funder: Spanish Ministry of Science, Innovation, and University. BFU2016-80570-R

Funder: Cancer Research UK (CRUK); doi:

Funder: Fundación Científica Asociación Española Contra el Cáncer (Scientific Foundation, Spanish Association Against Cancer); doi:


Article, /631/67/1347, /631/67/68, /13/1, /13/51, /38/39, /82/80, /96/106, /45/22, /45/90, article

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Nature Publishing Group UK
Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung) (P27361-B23, P27361-B23, P27361-B23)
Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación) (SAF2011-29530, SAF2011-29530, SAF2015-70553-R)