Gene expression microarray analysis of ZR75-1 human breast cancer cells ectopically expressing wild-type or mutant GATA3
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Paraic Kenny
PROVIDER: E-MTAB-7534 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The transcription factor GATA3 is a favorable prognostic indicator in estrogen receptor-M-NM-1 (ERM-NM-1)-positive breast tumors in which it participates with ERa and FOXA1 in a complex transcriptional regulatory program driving tumor growth. Paradoxically, GATA3 mutations are frequent in breast cancer and have been classified as drivers. To elucidate the contribution(s) of GATA3 alterations to oncogenesis, we studied two breast cancer cell lines, MCF7, which carries a heterozygous frameshift mutation in the second zinc finger of GATA3, and T47D, wild-type at this locus. Heterozygosity for the truncating mutation conferred protection from regulated turnover of GATA3, ERa and FOXA1 following estrogen stimulation. Thus, mutant GATA3 uncouples protein-level regulation of master regulatory transcription factors from hormone action. Consistent with increased protein stability, ChIP-seq profiling identified stronger accumulation of GATA3 in cells bearing the mutation, albeit with a similar distribution across the genome. We propose that this specific, cancer-derived mutation in GATA3 deregulates physiologic protein turnover, stabilizes GATA3 binding across the genome and modulates the response of mammary epithelial cells to hormone signaling, thus conferring a selective growth advantage. Genome-wide mapping of GATA3 in two cell lines. There were two biological replicates and unchipped (input) DNA was used as reference.
2014-04-01 | E-GEOD-51274 | biostudies-arrayexpress
Project description:The transcription factor GATA3 is a favorable prognostic indicator in estrogen receptor-α (ERα)-positive breast tumors in which it participates with ERa and FOXA1 in a complex transcriptional regulatory program driving tumor growth. Paradoxically, GATA3 mutations are frequent in breast cancer and have been classified as drivers. To elucidate the contribution(s) of GATA3 alterations to oncogenesis, we studied two breast cancer cell lines, MCF7, which carries a heterozygous frameshift mutation in the second zinc finger of GATA3, and T47D, wild-type at this locus. Heterozygosity for the truncating mutation conferred protection from regulated turnover of GATA3, ERa and FOXA1 following estrogen stimulation. Thus, mutant GATA3 uncouples protein-level regulation of master regulatory transcription factors from hormone action. Consistent with increased protein stability, ChIP-seq profiling identified stronger accumulation of GATA3 in cells bearing the mutation, albeit with a similar distribution across the genome. We propose that this specific, cancer-derived mutation in GATA3 deregulates physiologic protein turnover, stabilizes GATA3 binding across the genome and modulates the response of mammary epithelial cells to hormone signaling, thus conferring a selective growth advantage.
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Project description:Estrogen Receptor (ER) is a steroid hormone receptor that regulates epithelial genes in breast cancer. ER forms a regulatory network with the other transcription factors, FOXA1 and GATA3. GATA3 is known to be capable of specifying chromatin localization of FOXA1 and ER. GATA3 has been identified as one of the most frequently mutated genes in breast cancer. However, how GATA3 mutations impact this transcriptional network is unknown. Here we investigate the function of one of the recurrent patient-derived GATA3 mutations (R330fs) for this regulatory network. Genomic analysis indicates that the R330fs mutant can disrupt the cooperative action of ER, FOXA1, and GATA3, and induce chromatin relocalization of these factors. Relocalizations of ER and FOXA1 are associated with altered chromatin architectures leading to differential gene expression in the GATA3 mutant cells. These results suggest the active role of GATA3 mutants in ER positive breast tumors.
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