Dataset Information

Cancer-specific mutation of GATA3 disrupts the transcriptional regulatory network governed by Estrogen Receptor alpha, FOXA1 and GATA3.

ABSTRACT: Estrogen receptors (ER) are activated by the steroid hormone 17?-estradiol. Estrogen receptor alpha (ER-?) forms a regulatory network in mammary epithelial cells and in breast cancer with the transcription factors FOXA1 and GATA3. GATA3 is one of the most frequently mutated genes in breast cancer and is capable of specifying chromatin localization of FOXA1 and ER-?. How GATA3 mutations found in breast cancer impact genomic localization of ER-? and the transcriptional network downstream of ER-? and FOXA1 remains unclear. Here, we investigate the function of a recurrent patient-derived GATA3 mutation (R330fs) on this regulatory network. Genomic analysis indicates that the R330fs mutant can disrupt localization of ER-? and FOXA1. Loci co-bound by all three factors are enriched for genes integral to mammary gland development as well as epithelial cell biology. This gene set is differentially regulated in GATA3 mutant cells in culture and in tumors bearing similar mutations in vivo. The altered distribution of ER-? and FOXA1 in GATA3-mutant cells is associated with altered chromatin architecture, which leads to differential gene expression. These results suggest an active role for GATA3 zinc finger 2 mutants in ER-? positive breast tumors.

SUBMITTER: Takaku M

PROVIDER: S-EPMC7229857 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Cancer-specific mutation of GATA3 disrupts the transcriptional regulatory network governed by Estrogen Receptor alpha, FOXA1 and GATA3.

Takaku Motoki M Grimm Sara A SA De Kumar Bony B Bennett Brian D BD Wade Paul A PA

Nucleic acids research 20200501 9

Estrogen receptors (ER) are activated by the steroid hormone 17β-estradiol. Estrogen receptor alpha (ER-α) forms a regulatory network in mammary epithelial cells and in breast cancer with the transcription factors FOXA1 and GATA3. GATA3 is one of the most frequently mutated genes in breast cancer and is capable of specifying chromatin localization of FOXA1 and ER-α. How GATA3 mutations found in breast cancer impact genomic localization of ER-α and the transcriptional network downstream of ER-α a ...[more]

PMID: 32232341

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Project description:Breast cancer is the leading cause of death in female cancers, and what's worse, tamoxifen resistance occurs in almost 30% breast cancer patients and has seriously attenuated the therapeutic effect. It is widely studied that epigenetic regulation has played important role in the development of tamoxifen resistance. FOXA1 is a pioneer transcription factor that can translate epigenetic signature into transcription regulation and also drive genome-wide enhancer reprogramming in breast cancer. However, the chromatin super enhancer landscape orchestrated by FOXA1 and the key downstream targets of the FOXA1 oncogenic network in tamoxifen resistance remain elusive. Through analyzing the FOXA1 ChIP-seq data in tamoxifen sensitive MCF7 and tamoxifen resistant MCF7/TamR cells, we show that the FOXA1 chromatin occupancy is enhanced in both the promoter and enhancer regions, and the recruitment events may be E2 dependent in both MCF7 and MCF7/TamR cells. By integratively analyzing the FOXA1 ChIP-seq data and RNA-seq data of MCF7 and MCF7/TamR cells, we find that the enhanced or reduced FOXA1 chromatin binding densities may synchronize the transcriptional activity in tamoxifen resistance. Besides, we identify 1003 super enhancer associated protein coding genes and five super enhancer associated lncRNAs (ATP1A1-AS1, CASC11, CASC15, KCTD21-AS1, LINC00885) in tamoxifen resistance. By KM survival analysis, we find that high expression level of ATP1A1-AS1 and its sense transcript ATP1A1 indicates favorable clinical outcome among the luminal endocrine treated breast cancer patients. Further coexpression analysis indicates that ATP1A1-AS1 is significantly correlated with ATP1A1, and RT-qPCR results show that they both are downregulated in MCF7/TamR cells. Our study shows that the FOXA1 transcriptional regulatory network may promote the development of tamoxifen resistance, and identifies one super enhancer associated lncRNA ATP1A1-AS1 that may work as promising biomarker or drug target in tamoxifen resistance.

Dataset Information

Cancer-specific mutation of GATA3 disrupts the transcriptional regulatory network governed by Estrogen Receptor alpha, FOXA1 and GATA3.

Publications

Cancer-specific mutation of GATA3 disrupts the transcriptional regulatory network governed by Estrogen Receptor alpha, FOXA1 and GATA3.

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