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Cistromic re-programming by truncating GATA3 mutations promotes mesenchymal transformation in vitro, but not mammary tumour formation in mice

ABSTRACT: Cistromic re-programming by truncating GATA3 mutations promotes mesenchymal transformation in vitro, but not mammary tumour formation in mice

PROVIDER: PRJNA506681 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8239350.fastq.gz	Fastqsanger.gz
	SRR8239360.fastq.gz	Fastqsanger.gz
	SRR8239370.fastq.gz	Fastqsanger.gz
	SRR8239351.fastq.gz	Fastqsanger.gz
	SRR8239361.fastq.gz	Fastqsanger.gz

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Cistromic re-programming by truncating GATA3 mutations promotes mesenchymal transformation in vitro, but not mammary tumour formation in mice [ChIP-seq]

Project description:Heterozygous mutations in the transcription factor GATA3 are identified in 10-15% of all breast cancer cases. Most of these are protein-truncating mutations, concentrated within or downstream of the second GATA-type zinc-finger domain. Here, we investigated the functional consequences of expression of two truncated GATA3 mutants, in vitro in breast cancer cell lines and in vivo in the mouse mammary gland. We found that the truncated GATA3 mutants display altered DNA binding activity caused by preferred tethering through FOXA1. In addition, expression of the truncated GATA3 mutants reduces E-cadherin expression and promotes anchorage-independent growth in vitro. However, we could not identify any effects of truncated GATA3 expression on mammary gland development or mammary tumor formation in mice. Together, our results demonstrate that both truncated GATA3 mutants promote cistromic re-programming of GATA3 in vitro, but these mutants are not sufficient to induce tumor formation in mice.

2019-06-12 | GSE122847 | GEO

Cistromic re-programming by truncating GATA3 mutations promotes mesenchymal transformation in vitro, but not mammary tumour formation in mice [RNA-seq]

2019-06-12 | GSE122848 | GEO

Cistromic re-programming by truncating GATA3 mutations promotes mesenchymal transformation in vitro, but not mammary tumour formation in mice [RNA-seq]

Project description:Cistromic re-programming by truncating GATA3 mutations promotes mesenchymal transformation in vitro, but not mammary tumour formation in mice [RNA-seq]

| PRJNA506684 | ENA

Cistromic re-programming by truncating GATA3 mutations promotes mesenchymal transformation in vitro, but not mammary tumour formation in mice [ChIP-seq]

Project description:Cistromic re-programming by truncating GATA3 mutations promotes mesenchymal transformation in vitro, but not mammary tumour formation in mice [ChIP-seq]

| PRJNA506682 | ENA

Cistromic re-programming by truncating GATA3 mutations promotes mesenchymal transformation in vitro, but not mammary tumour formation in mice

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-06-12 | GSE122849 | GEO

Breast tumor specific mutation in GATA3 impacts protein stability and genomic location

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

Comparison of GATA3 mutant and GATA3 wild type isogenic MCF-7 and CAMA1 breast cancer cell lines

Project description:The GATA3 transcription factor is one of the most frequently mutated genes in breast cancer. Heterozygous mutations, largely frameshifting, are seen in 15% of estrogen receptor positive breast cancers, the subtype in which these mutations are almost exclusively found. Mouse studies have shown that Gata3 is critical for breast development and that GATA3 gene dosage affects breast tumor progression. Human patient data have shown that high Gata3 expression, a feature of luminal subtype breast cancers, is associated with a better prognosis. Although the frequency of GATA3 mutation suggests an important role in breast cancer development or progression, there is little understanding of how mutations in GATA3 affect its function in luminal breast epithelial cells and what gene expression changes result as a consequence of the mutations. Here, using gene editing, we have created two sets of isogenic human luminal breast cancer cell lines with and without a truncating GATA3 mutation. GATA3 mutation enhanced tumor growth in vivo but did not affect sensitivity to clinically used hormonal therapies or chemotherapeutic agents. We identified genes upregulated and downregulated in GATA3 mutant cells, a subset of which was concordantly differentially expressed in GATA3 mutant primary luminal breast cancers. Addback of mutant GATA3 recapitulated mutation-specific gene expression changes and enhanced soft agar colony formation, suggesting a gain of function for the mutant protein.

2018-01-12 | GSE101780 | GEO

Breast tumor specific mutation in GATA3 impacts protein stability and genomic location

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.

2014-04-01 | GSE51274 | GEO

The¬¬¬ androgen receptor interacts with GATA3 to transcriptionally regulate a luminal epithelial cell phenotype in breast cancer

Project description:Background: The androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive breast cancer, a role sustained in some ER negative breast cancers. Key factors dictating AR genomic activity in a breast context are largely unknown. Herein, we employed an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting co-regulatory proteins in ER positive and negative models of breast cancer to gain new insight into mechanisms of AR signaling in this disease. Results: The DNA-binding factor GATA3 is identified and validated as a novel AR interacting protein in breast cancer cells irrespective of ER status. AR activation by the natural ligand 5α-dihydrotestosterone (DHT) increases nuclear AR-GATA3 interactions, resulting in AR-dependent enrichment of GATA3 chromatin binding at a sub-set of genomic loci. Silencing GATA3 reduces but does not prevent AR DNA binding and transactivation of genes associated with AR/GATA3 co-occupied loci, indicating a co-regulatory role for GATA3 in AR signaling. DHT-induced AR/GATA3 binding coincides with upregulation of luminal differentiation genes, including EHF and KDM4B, established master regulators of a breast epithelial cell lineage. These findings are validated in a patient-derived xenograft model of breast cancer. Interaction between AR and GATA3 is also associated with AR-mediated growth inhibition in ER positive and ER negative breast cancer.

2024-01-30 | PXD047997 | Pride

GATA3 mutation disrupts functional network governed by Estrogen receptor, FOXA1 and GATA3

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.

2020-02-27 | GSE130703 | GEO

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