The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver.
作者： Natascha Hruschka , Mark Kalisz , Maria Subijana , Osvaldo Graña-Castro , Francisco Del Cano-Ochoa
DOI: 10.1038/S41388-020-1376-3
关键词:
摘要: 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 paradigm this. We investigated most common mutation (X308_Splice) five additional mutations, which converge neoprotein we called "neoGATA3," associated with excellent prognosis patients. Analysis available molecular data from >3000 breast cancer patients revealed dysregulation ER-dependent transcriptional response tumors carrying neoGATA3-generating mutations. Mechanistic studies vitro showed neoGATA3 interferes programs controlled by estrogen progesterone receptors, without fully abrogating them. ChIP-Seq analysis indicated ER binding reduced neoGATA3-expressing cells, especially at distal regions, suggesting fine tuning expression. This has opposite outputs distinct hormonal context, having pro- or anti-proliferative effects, depending on estrogen/progesterone ratio. Our call for functional analyses putative drivers to guide clinical application.
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