6533b834fe1ef96bd129d758
RESEARCH PRODUCT
The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver
Laia Paré BrunetBegoña BermejoOctavio BurguesDavid AndreuAna SagreraFrancisco X. RealIgor ChernukhinCarlos CaldasNatascha HruschkaOsvaldo Graña-castroSantiago Ramón-maiquesAurélien De ReynièsFrancisco Del Caño-ochoaSuet-feung ChinAleix PratAna LluchPaola MartinelliJoseph SuttonJason S. CarrollMaria Subijanasubject
0303 health sciencesGATA3CancerContext (language use)Biologymedicine.disease03 medical and health sciences0302 clinical medicineBreast cancer030220 oncology & carcinogenesisMutation (genetic algorithm)Cancer researchmedicinespliceTranscription factorGene030304 developmental biologydescription
AbstractAs the catalogue of oncogenic driver mutations is expanding, it is becoming clear that alterations in a given gene should not be lumped into one single class, since they might have different functions. The transcription factorGATA3is a paradigm of this. Here, we address the functions of the most commonGATA3mutation (X308_Splice) which generates a neoprotein that we designate as neoGATA3, associated with good patient prognosis. Based on extensive analyses of molecular and clinical data from approximately 3000 breast cancer patients, supported by mechanistic studiesin vitro, we show that neoGATA3 interferes with the transcriptional programs controlled by estrogen and progesterone receptors, without fully abrogating them. This has opposite outputs in the pre- or post-menopausal hormonal context, having pro- or anti-proliferative effects, respectively. NeoGATA3 is an example of a context- and stage-dependent driver mutation. Our data call for functional analyses of putative cancer drivers to guide clinical application.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-06-08 |