GATA3 zinc finger 2 mutations reprogram the breast cancer transcriptional network

Motoki Takaku, Sara A. Grimm, John D. Roberts, Kaliopi Chrysovergis, Brian D. Bennett, Page Myers, Lalith Perera, Charles J. Tucker, Charles M. Perou and Paul A. Wade ()
Additional contact information
Motoki Takaku: Research Triangle Park
Sara A. Grimm: Research Triangle Park
John D. Roberts: Research Triangle Park
Kaliopi Chrysovergis: Research Triangle Park
Brian D. Bennett: Research Triangle Park
Page Myers: Research Triangle Park
Lalith Perera: Research Triangle Park
Charles J. Tucker: Research Triangle Park
Charles M. Perou: University of North Carolina
Paul A. Wade: Research Triangle Park

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract GATA3 is frequently mutated in breast cancer; these mutations are widely presumed to be loss-of function despite a dearth of information regarding their effect on disease course or their mechanistic impact on the breast cancer transcriptional network. Here, we address molecular and clinical features associated with GATA3 mutations. A novel classification scheme defines distinct clinical features for patients bearing breast tumors with mutations in the second GATA3 zinc-finger (ZnFn2). An engineered ZnFn2 mutant cell line by CRISPR–Cas9 reveals that mutation of one allele of the GATA3 second zinc finger (ZnFn2) leads to loss of binding and decreased expression at a subset of genes, including Progesterone Receptor. At other loci, associated with epithelial to mesenchymal transition, gain of binding correlates with increased gene expression. These results demonstrate that not all GATA3 mutations are equivalent and that ZnFn2 mutations impact breast cancer through gain and loss-of function.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03478-4

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DOI: 10.1038/s41467-018-03478-4

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