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.
Highlights
Genomics studies have produced an expanding catalog of cancer-driving somatic mutations, which needs to be10 INCLIVA Biomedical Research Institute, Valencia, Spain Pathology Department, Hospital Clínico Universitario-CIBERONC, Valencia, Spain Laboratory of Proteomics and Protein Chemistry, Universitat Pompeu Fabra, Barcelona, Spain Oncology and Hematology Department, Hospital ClínicoUniversitario-CIBERONC, Valencia, Spain Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain Present address: Cancer Cell Signaling Department, Boehringer-Ingelheim RCV, Vienna, Austria translated into biological and clinically applicable knowledge [1]
We raised a polyclonal antiserum against the novel 44aa peptide, which recognized a shorter GATA3 protein of the expected size (37 kDa) exclusively in a tumor carrying the mutation and in cells transduced with the mutant cDNA (Fig. 1c and Supplementary Fig. 1b)
GATA3 is a paradigm of how genetic alterations in a given gene should not be lumped into a single class [5, 6]
Summary
Genomics studies have produced an expanding catalog of cancer-driving somatic mutations, which needs to be. We investigated the effects of the most prevalent GATA3 hotspot somatic mutation (X308_Splice) This mutation, like five additional ones producing partially or fully identical C-terminal peptides, correlates with better outcome in patients and is associated with a specific gene expression signature, characterized by altered ER-dependent transcriptional program. Combined analysis of patient-derived data and in vitro experiments with BC cell lines shows that the mutant protein—which we designate as “neoGATA3”— interferes with the function of both ER and PR, blunting, without abrogating, their downstream programs This has distinct biological outputs depending on the hormonal context: neoGATA3-expressing cells have a proliferative advantage when both estrogen and progesterone levels are high while they display a growth disadvantage when estrogen prevails. Our data suggest the existence of stage-dependent oncogenic effects of GATA3 driver mutations
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