title: 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.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Usary
authors.forename: Victor
authors.initials: V
authors.lastname: Llaca
authors.forename: Gamze
authors.initials: G
authors.lastname: Karaca
authors.forename: Shafaq
authors.initials: S
authors.lastname: Presswala
authors.forename: Mehmet
authors.initials: M
authors.lastname: Karaca
authors.forename: Xiaping
authors.initials: X
authors.lastname: He
authors.forename: Anita
authors.initials: A
authors.lastname: Langerød
authors.forename: Rolf
authors.initials: R
authors.lastname: Kåresen
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Oh
authors.forename: Lynn G
authors.initials: LG
authors.lastname: Dressler
authors.forename: Per E
authors.initials: PE
authors.lastname: Lønning
authors.forename: Robert L
authors.initials: RL
authors.lastname: Strausberg
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D002455:Cell Division; D002460:Cell Line; D017124:Conserved Sequence; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D050990:GATA3 Transcription Factor; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007668:Kidney; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011960:Receptors, Estrogen / Q000032:analysis; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000235:genetics*; D016335:Zinc Fingers
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D011960:Receptors, Estrogen; D015534:Trans-Activators