Novel estrogen-responsive genes (ERGs) for the evaluation of estrogenic activity
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ABSTRACT:
PROVIDER: PRJNA847584 | ENA |
REPOSITORIES: ENA
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Project description:Estrogen action is mediated by various genes including estrogen-responsive genes (ERGs). ERGs have been used as markers for gene expression and as reporter-genes, while gene expression profiling using a set of ERGs has been used as statistically reliable transcriptomic assays, such as DNA microarray assays and RNA-seq. However, the quality of ERGs has not been extensively examined. Here, we found a set of 300 ERGs newly identified by six sets of RNA-seq data obtained from estrogen-treated and control human breast cancer MCF-7 cells. The ERGs exhibited statistical stability as judged by the coefficient of variation (CV) analysis, and their usefulness as markers for estrogenic activity by examining the stability of data in the study of correlation analysis, and functional association with estrogen action through database searches. A set of the top 30 genes based on CV ranking were further evaluated quantitatively by RT-PCR and qualitatively by a functional analysis using GO and KEGG databases and by a mechanistic analysis to classify ERα/β-dependent or ER-independent types of transcriptional regulation. The 30 ERGs were characterized by (1) the enzymes, such as metabolic enzymes, proteases and protein kinases, (2) the genes with specific cell functions, such as cell-signaling mediators, tumor-suppressors and the roles in breast cancer, (3) the association with transcriptional regulation, and/or (4) estrogen-responsiveness. Therefore, the ERGs identified here could represent various cell functions and cell signaling pathways including estrogen signaling, and thus, would be useful to evaluate estrogenic activity.
2022-08-26 | GSE205784 | GEO
Project description:Estrogen action is mediated by various genes, including estrogen-responsive genes (ERGs). ERGs have been used as reporter-genes and markers for gene expression. Gene expression profiling using a set of ERGs has been used to examine statistically reliable transcriptomic assays such as DNA microarray assays and RNA sequencing (RNA-seq). However, the quality of ERGs has not been extensively examined. Here, we obtained a set of 300 ERGs that were newly identified by six sets of RNA-seq data from estrogen-treated and control human breast cancer MCF-7 cells. The ERGs exhibited statistical stability, which was based on the coefficient of variation (CV) analysis, correlation analysis, and examination of the functional association with estrogen action using database searches. A set of the top 30 genes based on CV ranking were further evaluated quantitatively by RT-PCR and qualitatively by a functional analysis using the GO and KEGG databases and by a mechanistic analysis to classify ERα/β-dependent or ER-independent types of transcriptional regulation. The 30 ERGs were characterized according to (1) the enzymes, such as metabolic enzymes, proteases, and protein kinases, (2) the genes with specific cell functions, such as cell-signaling mediators, tumor-suppressors, and the roles in breast cancer, (3) the association with transcriptional regulation, and (4) estrogen-responsiveness. Therefore, the ERGs identified here represent various cell functions and cell signaling pathways, including estrogen signaling, and thus, may be useful to evaluate estrogenic activity.
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Project description:Due to its high throughput nature, toxicogenomics can provide a broad picture of a toxic response, offering the ideal functional platform for grouping chemicals according to mechanistic similarity. In this way, toxicogenomics has found its way into predictive toxicology. However, so far, the predictive potential of toxicogenomics in an endocrine disruptive screening context has not been extensively examined. The aim of this study was to combine a toxicogenomics approach with an estrogen-sensitive MCF-7 cell system. In total, 18 compounds with endocrine disruptive potential were selected, of which 11 are listed as ICCVAM reference compounds for validation of estrogen receptor (ER) binding and transactivation assays. In this way, the grouping and classification potential of the gene expression profiles could be directly compared to the more classical estrogenicity screens, such as ER binding, ER transactivation and MCF-7 cell proliferation assays. Results indicated that this toxicogenomics approach was clearly capable of grouping compounds into strong, weak and non estrogenic groups. This demonstrates the value of toxicogenomics for evaluating gradual differences in related modes of action, in addition to the more common search for opposite modes of action. The chemical groups were represented by interesting marker genes such as PGR, ERBB2, CXCL12, AREG and EGR3, including some early-responsive (4h) potential biomarkers. These results open the discussion on the added value of a broader endpoint evaluation in estrogenicity screens provided by omics-techniques compared to the classical single endpoint based assays.
2015-10-01 | GSE16881 | GEO
Project description:We carried out a comparative study of the orally bioavailable investigational SERD elacestrant, versus fulvestrant, in models of endocrine sensitive and resistant BC harbouring varying genetic backgrounds. Both drugs showed comparable effects on tumour growth of ER+ patient-derived xenograft models harbouring several ESR1 mutations and elacestrant showed activity after acquired resistance to fulvestrant. Treatment with either drug showed similar impact on ER-cistrome, ER- interactome and suppression of estrogen-regulated genes, confirming the anti-estrogenic activity of elacestrant.
2022-08-01 | GSE190384 | GEO
Project description:We carried out a comparative study of the orally bioavailable investigational SERD elacestrant, versus fulvestrant, in models of endocrine sensitive and resistant BC harbouring varying genetic backgrounds. Both drugs showed comparable effects on tumour growth of ER+ patient-derived xenograft models harbouring several ESR1 mutations and elacestrant showed activity after acquired resistance to fulvestrant. Treatment with either drug showed similar impact on ER-cistrome, ER- interactome and suppression of estrogen-regulated genes, confirming the anti-estrogenic activity of elacestrant.
2022-08-01 | GSE190385 | GEO
Project description:To understand the complex mechanism of estrogen action, multiple assays based on different biological principles is important. Here, multiple assays based on cell, protein and transcription assays were used to evaluate estrogenic activity of soymilk extracts before and after fermentation, and four soy compounds, genistein and daidzein, and their glycosides, genistin and daidzin, respectively. The data obtained by a transcription assay, RNA-sequencing (RNA-seq), was further examined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database analysis to understand cell functions, i.e. biological processes and metabolic pathways. Among the cell functions identified, the sets of genes for cell division/cell cycle and DNA replication/DNA repair are significantly up-regulated, whereas those for autophagy are significantly down-regulated, which explains well the enhanced activity of cell proliferation by these materials. The applications of estrogenic activity of soymilk extracts and soy flavonoids, and the contribution of fermentation, include pharmacological benefits, such as bone protection/bone regeneration, cancer chemoprevention, neuroprotection and the treatment of menopausal syndromes.
2023-10-31 | GSE226627 | GEO
Project description:Both ovarian and pituitary hormones are required for the pubertal development of the mouse mammary gland. Estradiol directs ductal elongation and branching within the adipose stroma of the adolescent mouse mammary gland, while progesterone leads to tertiary branching and alveolar development. The purpose of this investigation was to identify the estrogen-responsive genes that are associated with estrogen-stimulated ductal elongation and branching in the mouse mammary gland in the absence of other ovarian hormones. We also wanted to determine if estrogen-responsive gene regulation at early stages of ductal elongation (ie. when ductal growth was minimal) was similar to those regulated after significant ductal elongation had occurred. To identify estrogen-regulated genes, ovariectomized prepubertal mice were exposed to 17beta-estradiol for four weeks, and mammary gland global gene expression analyzed by microarray analysis at various points during this time course. We determined that while many genes are regulated in all weeks of treatment, there remained a subset of genes that was uniquely regulated at each time-point. This observation was reflected in the biological functions of these genes; some categories were represented in all weeks of treatment while others were specific to only certain time-points. We have also identified estradiol-responsive genes in the mouse mammary gland that co-express with Estrogen Receptor alpha in human breast cancer, which may represent novel effectors of estrogen action and/or biomarkers for the progression of estrogen-dependent cancers and other estrogen-driven diseases.
2008-12-01 | GSE4647 | GEO
Project description:Worldwide an ever-increasing number of women are prescribed estrogen modulating therapies (EMTs) for the treatment of breast cancer. In parallel, aging of the global population of women will contribute to risk of both breast cancer and Alzheimer’s disease. To address the impact of anti-estrogen therapies on risk of Alzheimer’s and neural function, we conducted medical informatic and molecular pharmacology analyses to determine the impact of EMTs on risk of Alzheimer’s followed by determination of EMT estrogenic mechanisms of action in neurons. In a propensity matched data set of 260,232 women with breast cancer, medical informatic analyses indicated that EMTs were associated with reduced risk of AD which was driven by patients receiving tamoxifen or aromatase inhibitors whereas raloxifene was ineffective independently validating earlier reports. Mechanistically, a comparative analysis of EMTs vs estradiol was conducted to determine whether EMTs exerted estrogenic action in neural cells in-vitro and in brain in-vivo. Outcomes of mechanistic analyses indicated that select EMTs induced estrogenic action and pathways in neural cells including promoting neuronal morphological plasticity, electrophysiological indicators of synaptic connectivity, mitochondrial number and function and induction of transcriptomic pathways consistent with estrogenic outcomes. Collectively, these data provide both clinical and mechanistic data indicating that select EMTs exert estrogenic agonist action in neural tissue that are associated with reduced risk of Alzheimer’s disease while simultaneously acting as effective estrogen receptor antagonists in breast.
2023-11-01 | GSE241054 | GEO
Project description:Spermatogenesis occurs in the seminiferous epithelium that shows presence of estrogen receptors alpha (ERα) and beta (ERβ), both of which regulate gene transcription by binding to the DNA. Hormone responsive phases of spermatogenesis are well documented; yet, the genes regulated remain inexplicit. To study the regulation of genes by estrogen in male germ cells, we performed chromatin immunoprecipitation (ChIP) sequencing for ERα and ERβ under normal physiological conditions. We observed a total of 27,221 peaks in ERα and 20,926 peaks in ERβ. Majority of the peaks were present in the intronic regions and located 20kb upstream or downstream from the transcription start site (TSS). Upon pathway analysis, the genes enriched showed involvement in several biological pathways. Genes involved in pathways whose role in spermatogenesis is unexplored were validated; these included prolactin, GnRH and oxytocin signalling. All the genes showed presence of estrogen response elements (EREs) and majority of them showed significant enrichment by ChIP-qPCR. Functional validation using seminiferous tubule culture after treatment with receptor specific agonist and antagonist confirmed the regulation of these genes by estrogen through its receptors. This study provides new insights about the estrogen regulated genes during spermatogenesis.
2020-03-17 | GSE147079 | GEO
Project description:Cell-specific transcriptional regulations exerted by the estrogen (E2) receptor alpha (ER) heavily rely upon timely and spatially coordinated processes. We engaged a comparative analysis of such dynamic molecular events at the TFF locus harbouring a cluster of genes co-regulated by E2, in two distinct breast cancer cell lines. Using a combination of methods, we show that the recruitment of ER on cell-specific sites triggers dynamic local modifications of chromatin, which are coordinated in time all along the locus. DNA-FISH experiments further demonstrate that these changes are associated with an E2-dependent reduction in plasticity of this genomic region and are dependent upon cohesin. Importantly, 3C/4C experiments and the use of triplex forming oligonucleotides (TFOs) allowed us to precisely map the three-dimensional network of regulatory events that permits the estrogenic response of this genomic region. These data also evidenced an unexpected functional redundancy of enhancers. Independent duplicate array series, using on one array pooled ChIP triplicates prepared from separate MDA::ER or MCF-7 cell cultures treated with estradiol for 50 minutes.
2014-05-06 | E-GEOD-32132 | biostudies-arrayexpress