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| Status |
Public on Apr 01, 2014 |
| Title |
Breast tumor specific mutation in GATA3 impacts protein stability and genomic location |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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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| Overall design |
Genome-wide mapping of GATA3 in two cell lines. There were two biological replicates and unchipped (input) DNA was used as reference.
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| Contributor(s) |
Adomas AB, Grimm SA, Malone C, Takaku M, Sims JK, Wade PA |
| Citation(s) |
24758297 |
| Submission date |
Sep 30, 2013 |
| Last update date |
May 15, 2019 |
| Contact name |
Paul A Wade |
| E-mail(s) |
wadep2@niehs.nih.gov
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| Phone |
919-541-3392
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| Organization name |
NIEHS
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| Department |
Laboratory of Molecular Carcinogenesis
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| Street address |
111 TW Alexander Drive
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| City |
Research Triangle Park |
| State/province |
NC |
| ZIP/Postal code |
27709 |
| Country |
USA |
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| Platforms (1) |
| GPL10999 |
Illumina Genome Analyzer IIx (Homo sapiens) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA222284 |
| SRA |
SRP030633 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE51274_MCF7.GATA3.bedGraph.gz |
429.6 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE51274_MCF7.GATA3.peaks.bed.gz |
173.6 Kb |
(ftp)(http) |
BED |
| GSE51274_MCF7.input.bedGraph.gz |
423.9 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE51274_T47D.GATA3.bedGraph.gz |
421.2 Mb |
(ftp)(http) |
BEDGRAPH |
| GSE51274_T47D.GATA3.peaks.bed.gz |
96.5 Kb |
(ftp)(http) |
BED |
| GSE51274_T47D.input.bedGraph.gz |
408.3 Mb |
(ftp)(http) |
BEDGRAPH |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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