GATA3 Zinc Finger 2 Mutations Reprogram the Breast Cancer Transcriptional Network

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Mar 15

PMID 29535312

Citations 46

Authors

Motoki Takaku

Sara A Grimm

John D Roberts

Kaliopi Chrysovergis

Brian D Bennett

Page Myers

Lalith Perera

Charles J Tucker

Charles M Perou

Paul A Wade

Affiliations

Soon will be listed here.

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.

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