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

Authors
  • Hruschka, Natascha1
  • Kalisz, Mark2
  • Subijana, Maria1
  • Graña-Castro, Osvaldo3
  • Del Cano-Ochoa, Francisco4
  • Brunet, Laia Paré5, 6
  • Chernukhin, Igor7
  • Sagrera, Ana2
  • De Reynies, Aurelien8
  • Kloesch, Bernhard1
  • Chin, Suet-Feung7
  • Burgués, Octavio9, 10
  • Andreu, David11
  • Bermejo, Begoña9, 10
  • Cejalvo, Juan Miguel9, 10
  • Sutton, Joe7
  • Caldas, Carlos7
  • Ramón-Maiques, Santiago4
  • Carroll, Jason S.7
  • Prat, Aleix5, 6
  • And 2 more
  • 1 Medical University Vienna, Comprehensive Cancer Center,
  • 2 Spanish National Cancer Research Centre-CNIO, CIBERONC,
  • 3 Spanish National Cancer Research Centre-CNIO,
  • 4 Centro de Biología Molecular Severo Ochoa (CSIC-UAM),
  • 5 Hospital Clínic,
  • 6 Translational Genomics and Targeted Therapeutics in Solid Tumors, IDIBAPS,
  • 7 University of Cambridge,
  • 8 Ligue Nationale Contre le Cancer,
  • 9 INCLIVA Biomedical Research Institute, Valencia, Spain
  • 10 Hospital Clínico Universitario-CIBERONC,
  • 11 Universitat Pompeu Fabra,
  • 12 Boehringer-Ingelheim RCV,
Type
Published Article
Journal
Oncogene
Publisher
Nature Publishing Group UK
Publication Date
Jun 25, 2020
Volume
39
Issue
32
Pages
5455–5467
Identifiers
DOI: 10.1038/s41388-020-1376-3
PMID: 32587399
PMCID: PMC7410826
Source
PubMed Central
Keywords
License
Unknown

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.

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