The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver.
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
24
03
2020
accepted:
16
06
2020
revised:
11
06
2020
pubmed:
27
6
2020
medline:
1
12
2020
entrez:
27
6
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32587399
doi: 10.1038/s41388-020-1376-3
pii: 10.1038/s41388-020-1376-3
pmc: PMC7410826
doi:
Substances chimiques
GATA3 Transcription Factor
0
GATA3 protein, human
0
RNA, Messenger
0
Receptors, Estrogen
0
Receptors, Progesterone
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5455-5467Références
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