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Mutation of GATA3 in human breast tumors

Abstract

GATA3 is an essential transcription factor that was first identified as a regulator of immune cell function. In recent microarray analyses of human breast tumors, both normal breast luminal epithelium and estrogen receptor (ESR1)-positive tumors showed high expression of GATA3. We sequenced genomic DNA from 111 breast tumors and three breast-tumor-derived cell lines and identified somatic mutations of GATA3 in five tumors and the MCF-7 cell line. These mutations cluster in the vicinity of the highly conserved second zinc-finger that is required for DNA binding. In addition to these five, we identified using cDNA sequencing a unique mis-splicing variant that caused a frameshift mutation. One of the somatic mutations we identified was identical to a germline GATA3 mutation reported in two kindreds with HDR syndrome/OMIM #146255, which is an autosomal dominant syndrome caused by the haplo-insufficiency of GATA3. The ectopic expression of GATA3 in human 293T cells caused the induction of 73 genes including six cytokeratins, and inhibited cell line doubling times. These data suggest that GATA3 is involved in growth control and the maintenance of the differentiated state in epithelial cells, and that GATA3 variants may contribute to tumorigenesis in ESR1-positive breast tumors.

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Acknowledgements

We wish to thank Jerry Shay (UTSW) for the ME16C cell line. We also thank Phil Bernard (Univ. of Utah) and Juan Palazzo (Thomas Jefferson Univ.) for contributing breast tumor samples to this study. This work was supported by funds from the NCI Breast SPORE program to UNC-CH (C.M.P. P50-CA58223-09A1), The Norwegian Cancer Society (A.-L. B-D D99061), the Research Council of Norway (A.-L. B-D 137012/310 and 155218/30) and the NCI CGAP Project (S.C.). We also wish to acknowledge the technical assistance and support of the Tissue Procurement and Analysis Facility of UNC-CH.

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Correspondence to Charles M Perou.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Usary, J., Llaca, V., Karaca, G. et al. Mutation of GATA3 in human breast tumors. Oncogene 23, 7669–7678 (2004). https://doi.org/10.1038/sj.onc.1207966

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