Journal Article

GATA3 zinc finger 2 mutations reprogram the breast cancer transcriptional network

Roberts, John D., Takaku, Motoki, Chrysovergis, Kaliopi, Grimm, Sara A., Perou, Charles M., Myers, Page, Tucker, Charles J., Bennett, Brian D., Perera, Lalith, Wade, Paul A.

2018

Overview

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. In breast cancer GATA3 is known to be frequently mutated, but the function of these mutations is unclear. Here, the authors utilise CRISPR-Cas9 to model frame-shift mutations in zinc finger 2 of GATA3, highlighting that GATA3 mutation can have gain- or loss-of function effects in breast cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/15 / 38/39 / 45 / 45/91 / 59 / 59/5 / 631/337/572/2102 / 631/67/1347 / 631/67/68/2486 / Animals / Binding / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Cancer / Cellular Reprogramming / CRISPR / Female / Frameshift Mutation / GATA-3 protein / GATA3 Transcription Factor - genetics / GATA3 Transcription Factor - metabolism / Gene Editing / Gene expression / Gene Expression Regulation, Neoplastic / Humanities and Social Sciences / Humans / Mammary Neoplasms, Experimental / MCF-7 Cells / Mesenchyme / Mice, Inbred BALB C / Mice, Nude / multidisciplinary / Mutation / Neoplasm Transplantation / Progesterone / Receptors, Progesterone - metabolism / Science / Science (multidisciplinary) / Transcription / Tumors / Zinc / Zinc finger proteins / Zinc Fingers - genetics