The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver
Natascha Hruschka, Mark Kalisz, Maria Subijana, Osvaldo Graña‐Castro, Francisco del Caño‐Ochoa, Laia Paré Brunet, Igor Chernukhin, Ana Sagrera, Aurélien de Reyniès, Bernhard Kloesch, Suet‐Feung Chin, Octavio Burgués, David Andreu, Begoña Bermejo, Juan Miguel Cejalvo, Joe Sutton, Carlos Caldas, Santiago Ramón‐Maiques, Jason S. Carroll, Aleix Prat, Francisco X. Real, Paola Martinelli
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.