The oncogenomic function of androgen receptor in esophageal squamous cell carcinoma is directed by GATA3
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ABSTRACT:
PROVIDER: PRJNA597367 | ENA |
REPOSITORIES: ENA
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Project description:Esophageal squamous cell carcinoma (ESCC) is the sixth leading cause of cancer death worldwide. Emerging evidence suggests that the androgen receptor (AR) is involved in ESCC tumorigenesis. However, how AR exerts its genomic functions in ESCC remains unknown. Here, by defining AR cistromes and analyzing androgen-regulated transcriptomes, we find that AR downregulates the majority of its target genes in ESCC cells. We further find that the pioneer factor GATA3 governs AR-repressed transcription by recruiting SMRT/HDAC3 co-repressors to target gene loci. Importantly, genetic inhibition of GATA3 or pharmacological inhibition of AR/HDAC3 relieves AR-mediated gene repression, leading to ESCC cell growth inhibition in vitro and in vivo. Our findings reveal molecular mechanisms underlying the oncogenomic function of AR in ESCC and identify the GATA3-directed AR transcriptional repression program as a therapeutic target for ESCC.
2020-10-21 | GSE142556 | GEO
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
Project description:Delineating intratumoural heterogeneity and neoantigen-directed immune escape in Esophageal Squamous Cell Carcinoma
| EGAS00001003832 | EGA
Project description:Our aim is to identify frequent genomic aberrations both in ESCC and esophageal dysplasia, and to discover important copy number-driving genes and microRNAs in ESCC. We carried out array-based comparative genomic hybridization (array CGH) on 59 ESCC resection samples and 16 dysplasia biopsy samples. Expression of genes at 11q13.3 was analyzed by real-time PCR and immunohistochemistry (IHC). Integrated analysis was performed to identify genes or microRNAs with copy number-expression correlations. Two group experiment, esophageal dysplasia vs. esophageal squamous cell carcinoma. Biological replicates: 16 dysplasias vs. 59 carcinomas
2013-04-29 | E-GEOD-46452 | biostudies-arrayexpress
Project description:Profiles of esophageal squamous cell carcinoma and normal esophageal normal epithelium normal cell line. Analysis provides validation of novel microRNA targets prediction algorithms. esophageal squamous cell carcinoma:14, normal epithelium cell:2
2016-09-01 | E-GEOD-23964 | biostudies-arrayexpress
Project description:Preoperative chemoradiotherapy (CRT) followed by surgery has been proved to improve esophageal squamous cell carcinoma (ESCC) patientsM-bM-^@M-^Y survival in comparison with surgery alone. However, the outcomes of CRT are heterogeneous, and no clinical or pathological method could predict CRT response. We aim to identify mRNA markers for ESCC CRT-response prediction through gene expression analyses. Gene expression analyses were performed on pretreatment cancer biopsies from 28 ESCCs who received neoadjuvant CRT and surgery and 10 normal esophageal epithelia using Affymetrix U133 Plus 2.0 arrays.
2014-08-01 | E-GEOD-45670 | biostudies-arrayexpress
Project description:This study was designed to identify genes aberrantly expressed in esophageal squamous cell carcinoma (ESCC) cells. Three esophageal squamous cell carcinoma-derived cell lines and one normal human esophageal squamous cell line were analyzed.
2014-09-20 | E-GEOD-61587 | biostudies-arrayexpress
Project description:GATA3 transcription factor is considered critical for luminal development and differentiation in normal and malignant mammary epithelial cells (MECs). The androgen receptor (AR) has also been associated with luminal gene expression profiles in breast cancer, independent of the estrogen receptor (ER), and has been shown to promote a basal to luminal phenotype transition in mouse MECs. To date, the potential interaction of GATA3 and AR in transcriptional regulation of lineage driver genes in breast cancer has never been investigated. Our unbiased proteomic analysis identified GATA3 as a novel AR interacting protein in a variety of breast cancer cell types regardless of ER expression. We showed that AR and GATA3 interact in the cytoplasm and nucleus of normal and malignant breast epithelia, an interaction increased by androgen treatment. Androgen stimulation of breast cancer cells also induced nuclear translocation of AR and GATA3 and resulted in enrichment of co-localized AR and GATA3 chromatin binding events. Using ER+ and/or ER- breast cancer cell lines and ER+ patient-derived xenograft (PDX) models of breast cancer, we identified a conserved subset of AR agonist-induced AR and GATA3 co-occupied cis-regulatory elements across all models. Knockdown experiments indicated that GATA3 acts as an AR co-regulator to upregulate transcription of known luminal-lineage genes (e.g. EHF, AQP3, and KDM4B) and downregulate basal-lineage genes (e.g. SMAD3 and ELK3). Also, we showed an induction in the chromatin accessibility at those subsets of common AR-GATA3 cis-regulatory elements, which drive the luminal lineage identity in breast cancer upon androgen stimulation. Collectively, AR-GATA3 interaction and function provide a mechanism underpinning epithelial breast cancer cells that are classified as having a luminal mature transcriptome independent of ER status, through regulating the expression of lineage-restricted markers.
2023-12-21 | GSE178253 | GEO
Project description:GATA3 transcription factor is considered critical for luminal development and differentiation in normal and malignant mammary epithelial cells (MECs). The androgen receptor (AR) has also been associated with luminal gene expression profiles in breast cancer, independent of the estrogen receptor (ER), and has been shown to promote a basal to luminal phenotype transition in mouse MECs. To date, the potential interaction of GATA3 and AR in transcriptional regulation of lineage driver genes in breast cancer has never been investigated. Our unbiased proteomic analysis identified GATA3 as a novel AR interacting protein in a variety of breast cancer cell types regardless of ER expression. We showed that AR and GATA3 interact in the cytoplasm and nucleus of normal and malignant breast epithelia, an interaction increased by androgen treatment. Androgen stimulation of breast cancer cells also induced nuclear translocation of AR and GATA3 and resulted in enrichment of co-localized AR and GATA3 chromatin binding events. Using ER+ and/or ER- breast cancer cell lines and ER+ patient-derived xenograft (PDX) models of breast cancer, we identified a conserved subset of AR agonist-induced AR and GATA3 co-occupied cis-regulatory elements across all models. Knockdown experiments indicated that GATA3 acts as an AR co-regulator to upregulate transcription of known luminal-lineage genes (e.g. EHF, AQP3, and KDM4B) and downregulate basal-lineage genes (e.g. SMAD3 and ELK3). Also, we showed an induction in the chromatin accessibility at those subsets of common AR-GATA3 cis-regulatory elements, which drive the luminal lineage identity in breast cancer upon androgen stimulation. Collectively, AR-GATA3 interaction and function provide a mechanism underpinning epithelial breast cancer cells that are classified as having a luminal mature transcriptome independent of ER status, through regulating the expression of lineage-restricted markers.
2023-12-21 | GSE178248 | GEO
Project description:GATA3 transcription factor is considered critical for luminal development and differentiation in normal and malignant mammary epithelial cells (MECs). The androgen receptor (AR) has also been associated with luminal gene expression profiles in breast cancer, independent of the estrogen receptor (ER), and has been shown to promote a basal to luminal phenotype transition in mouse MECs. To date, the potential interaction of GATA3 and AR in transcriptional regulation of lineage driver genes in breast cancer has never been investigated. Our unbiased proteomic analysis identified GATA3 as a novel AR interacting protein in a variety of breast cancer cell types regardless of ER expression. We showed that AR and GATA3 interact in the cytoplasm and nucleus of normal and malignant breast epithelia, an interaction increased by androgen treatment. Androgen stimulation of breast cancer cells also induced nuclear translocation of AR and GATA3 and resulted in enrichment of co-localized AR and GATA3 chromatin binding events. Using ER+ and/or ER- breast cancer cell lines and ER+ patient-derived xenograft (PDX) models of breast cancer, we identified a conserved subset of AR agonist-induced AR and GATA3 co-occupied cis-regulatory elements across all models. Knockdown experiments indicated that GATA3 acts as an AR co-regulator to upregulate transcription of known luminal-lineage genes (e.g. EHF, AQP3, and KDM4B) and downregulate basal-lineage genes (e.g. SMAD3 and ELK3). Also, we showed an induction in the chromatin accessibility at those subsets of common AR-GATA3 cis-regulatory elements, which drive the luminal lineage identity in breast cancer upon androgen stimulation. Collectively, AR-GATA3 interaction and function provide a mechanism underpinning epithelial breast cancer cells that are classified as having a luminal mature transcriptome independent of ER status, through regulating the expression of lineage-restricted markers.
2023-12-21 | GSE178254 | GEO