2026-04-29T04:09:21Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/181892024-11-29T15:47:54Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Hruschka, Natascha
author
Kalisz, Mark
author
Subijana, Maria
author
Graña-Castro, Osvaldo
author
Del Cano-Ochoa, Francisco
author
Brunet, Laia Paré
author
Chernukhin, Igor
author
Sagrera, Ana
author
De Reynies, Aurelien
author
Kloesch, Bernhard
author
Chin, Suet-Feung
author
Burgués, Octavio
author
Andreu, David
author
Bermejo, Begoña
author
Cejalvo, Juan Miguel
author
Sutton, Joe
author
Caldas, Carlos
author
Ramón-Maiques, Santiago
author
Carroll, Jason S
author
Prat, Aleix
author
Real Arribas, Francisco
author
Martinelli, Paola
funder
Ministerio de Ciencia, Innovación y Universidades (España)
funder
FWF Austrian Science Fund
funder
Institute of Cancer Research of the Medical University Vienna
2024-02-13T11:10:29Z
2024-02-13T11:10:29Z
2020-08
Oncogene . 2020;39(32):5455-5467.
http://hdl.handle.net/20.500.12105/18189
32587399
10.1038/s41388-020-1376-3
1476-5594
Oncogene
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410826/
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.
eng
The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver.
journal article
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