Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA335817 | ENA |
REPOSITORIES: ENA
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Project description:BCR/ABL1-Dependent Transcriptional Response Reveals Enrichment for Genes Involved in Negative Feedback Regulation
| PRJNA108487 | ENA
Project description:Estrogen receptor alpha (ERalpha) is a ligand-dependent transcription factor that plays an important role in breast cancer. Estrogen-dependent gene regulation by ERalpha can be mediated by interaction with other DNA-binding proteins, such as activator protein-1 (AP-1). The nature of such interactions in mediating the estrogen response in breast cancer cells remains unclear. Here we show that knockdown of c-Fos, a component of the transcription factor AP-1, attenuates the expression of 37% of all estrogen-regulated genes, suggesting that AP-1 is a fundamental factor for ERalpha-mediated transcription. Additionally, knockdown of c-Fos affected the expression of a number of genes that were not regulated by estrogen. Pathway analysis reveals that silencing of c-Fos downregulates an E2F1-dependent pro-proliferative gene network. Thus, modulation of the E2F1 pathway by c-Fos represents a novel mechanism by which c-Fos enhances breast cancer cell proliferation. Furthermore, we show that c-Fos and ERalpha can cooperate in regulating E2F1 gene expression by binding to regulatory elements in the E2F1 promoter. To start to dissect the molecular details of the cross-talk between AP-1 and estrogen signaling, we identify a novel ERalpha/AP-1 target, PKIB (cAMP-dependent protein kinase inhibitor-beta), which is overexpressed in ERalpha-positive breast cancer tissues. Knockdown of PKIB by siRNA results in drastic growth suppression of breast cancer cells. Collectively, our findings support AP-1 as a critical factor that governs estrogen-dependent gene expression and breast cancer proliferation programs. MCF-7 cells were transfected with a control siRNA or with the pool of siRNAs targeting c-Fos for 72 h and were then treated with vehicle or E2 for 24 h, and global gene expression profiles were assessed. Three or four biological replicates were used for each group.
2012-08-05 | E-GEOD-36586 | biostudies-arrayexpress
Project description:The estrogen receptor-α (ERα) is a transcription factor which plays a critical role in controlling cell proliferation and tumorigenesis by recruiting various cofactors to estrogen response elements (EREs) to induce or repress gene transcription. A deeper understanding of these transcriptional mechanisms may uncover novel therapeutic targets for ERα-dependent cancers. Here we show for the first time that BRD4 regulates ERα−induced gene expression by affecting elongation-associated phosphorylation of RNA Polymerase II (RNAPII P-Ser2) and histone H2B monoubiquitination (H2Bub1). Consistently, BRD4 activity is required for estrogen-induced proliferation of ER+ breast and endometrial cancer cells and uterine growth in mice. Genome-wide occupancy studies revealed an enrichment of BRD4 on transcriptional start sites as well as EREs enriched for H3K27ac and demonstrate a requirement for BRD4 for H2B monoubiquitination in the transcribed region of estrogen-responsive genes. Importantly, we further demonstrate that BRD4 occupancy correlates with active mRNA transcription and is required for the production of ERα-dependent enhancer RNAs (eRNAs). These results uncover BRD4 as a central regulator of ERα function and potential therapeutic target. ChIP-sequencing of BRD4, ERα and H2Bub1 in MCF7 cells treated with +/- estrogen treatment and or +/- JQ1 treatment in triplicates.
2014-07-10 | E-GEOD-55921 | biostudies-arrayexpress
Project description:Purpose:The study aimed to recognize potential molecular targets and signal pathways whereby phenolic environmental estrogen promotes the proliferation of uterine leiomyoma cells Methods:Primary cultured cell lines were treated with 0.1% DMSO, 10.0 μmol/L BPA, and 32.0 μmol/L NP for 48 h before RNA-seq was performed. Differentially expressed genes affected by BPA and NP were selected. Then, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and Protein-protein Interaction (PPI) analysis were performed. Quantitative real-time polymerase chain reaction (q-PCR) was used to verify the differentially expressed genes Results:In comparison with the control group, 739 differentially expressed mRNAs were identified in the BPA intervention group and the NP intervention group. GO enrichment analysis results show that the most enriched GO terms were connective tissue development and G1/S transition of mitotic cell cycle, and extracellular matrix. The results of KEGG enrichment analysis showed that differentially expressed mRNA was enriched mainly in three primary pathways, including environmental information processing, human diseases, and cellular processes. The cell cycle, PI3K-Akt signaling pathway, pathways in cancer, and TGF-beta signaling pathway are significantly enriched. Conclusions:Phenolic environmental estrogens may promote the proliferation and cell cycle progression of uterine leiomyoma cells through rapid non-genomic ER signaling, which leads to disordered cell cycle regulation and accelerates the transition of the cell cycle from G0/G1 phase to S phase. In addition, as an external harmful stimulant, phenolic estrogen promotes the upregulation of inflammatory factors in uterine leiomyomas.
2021-04-27 | GSE173334 | GEO
Project description:Altered expression of microRNAs (miRNAs), an abundant class of small non-protein-coding RNAs that mostly function as negative regulators of protein-coding gene expression, is common in cancer. Here we analyze the regulation of miRNA expression in response to estrogen, a steroid hormone that is involved in the development and progression of breast carcinomas and that is acting via the estrogen receptors (ER) transcription factors. We set out to thoroughly describe miRNA expression, by using miRNA microarrays and real time RTPCR experiments, in various breast tumor cell lines in which estrogen signaling has been induced by 17β-estradiol (E2). We show that the expression of a broad set of miRNAs decreases following E2 treatment in an ER-dependent manner. We further show that enforced expression of several of the repressed miRNAs reduces E2-dependent cell growth, thus linking expression of specific miRNAs with estrogen-dependent cellular response. In addition, a transcriptome analysis revealed that the E2-repressed miR-26a and miR-181a regulate many genes associated with cell growth and proliferation, including the progesterone receptor gene, a key actor in estrogen signaling. Strikingly, miRNA expression is also regulated in breast cancers of women who had received antiestrogen neoadjuvant therapy thereby showing an estrogen-dependent in vivo regulation of miRNA expression. Overall, our data indicates that the extensive alterations in miRNA regulation upon estrogen signalling pathway plays a key role in estrogen-dependent functions and highlights the utility of considering miRNA expression in the understanding of antiestrogen resistance of breast cancer. 9 samples analyzed. Triplicates were done. MCF-7+miR26a+E2 (n=1 to 3) ; MCF7+miRctrl+E2 (n=1 to 3) ; MCF7+miRctrl+vehicle (n=1 to 3). We generated pairwise comparisons using EASANA from GenoSplice technology: MCF-7+miR26a+E2 versus MCF7+miRctrl+E2 and MCF-7+miRctrl+E2 versus MCF7+miRctrl+vehicle. Fold change ≥1.5 were selected.
2009-08-04 | E-GEOD-17460 | biostudies-arrayexpress
Project description:The estrogen receptor-M-NM-1 (ERM-NM-1) is a transcription factor which plays a critical role in controlling cell proliferation and tumorigenesis by recruiting various cofactors to estrogen response elements (EREs) to induce or repress gene transcription. A deeper understanding of these transcriptional mechanisms may uncover novel therapeutic targets for ERM-NM-1-dependent cancers. Here we show for the first time that BRD4 regulates ERM-NM-1M-bM-^HM-^Rinduced gene expression by affecting elongation-associated phosphorylation of RNA Polymerase II (RNAPII P-Ser2) and histone H2B monoubiquitination (H2Bub1). Consistently, BRD4 activity is required for estrogen-induced proliferation of ER+ breast and endometrial cancer cells and uterine growth in mice. Genome-wide occupancy studies revealed an enrichment of BRD4 on transcriptional start sites as well as EREs enriched for H3K27ac and demonstrate a requirement for BRD4 for H2B monoubiquitination in the transcribed region of estrogen-responsive genes. Importantly, we further demonstrate that BRD4 occupancy correlates with active mRNA transcription and is required for the production of ERM-NM-1-dependent enhancer RNAs (eRNAs). These results uncover BRD4 as a central regulator of ERM-NM-1 function and potential therapeutic target. mRNA expression profiles of MCF7 cells treated with +/- estrogen treatment under negative control siRNA, BRD4 siRNA or JQ1 treatment, in duplicates.
2014-07-10 | E-GEOD-55922 | biostudies-arrayexpress
Project description:Under current models for signal-dependent transcription in eukaryotes, DNA-binding activator proteins regulate the recruitment of RNA polymerase II (Pol II) to a set of target promoters. Yet, recent studies, as well as our results herein, show that Pol II is widely distributed (i.e., "preloaded") at the promoters of many genes prior to specific signaling events. How Pol II recruitment and Pol II preloading fit within a unified model of gene regulation is unclear. In addition, the mechanisms through which cellular signals activate preloaded Pol II across mammalian genomes remain largely unknown. Here we show that the predominant genomic outcome of estrogen signaling is the post-recruitment regulation of Pol II activity through phosphorylation, rather than recruitment of Pol II. Furthermore, we show that negative elongation factor (NELF) binds to estrogen target promoters in conjunction with preloaded Pol II and represses gene expression until the appropriate signal is received. Finally, our studies reveal that the estrogen-dependent activation of preloaded Pol II facilitates rapid transcriptional and post-transcriptional responses which play important physiological roles in regulating estrogen signaling itself. Our results reveal a broad use of post-recruitment Pol II regulation by the estrogen signaling pathway, a mode of regulation that is likely to apply to a wide variety of signal-regulated pathways. ChIP-chip analysis for RNA Pol II, Ser5 phosphorylated RNA Pol II and NELF-A in MCF7 breast cancer cells.
2010-05-14 | E-GEOD-13051 | biostudies-arrayexpress
Project description:<p>The genomic evolution of breast cancers exposed to systemic therapy and its effects on clinical outcome have not been broadly characterized. We integrated the genomic sequencing of 1918 breast cancers, including 1501 hormone receptor-positive tumors, with detailed clinical information and treatment outcomes. Functional mutations in ERBB2 and loss-of-function mutations in NF1 were more than twice as common in post-endocrine therapy tumors compared to treatment-naive tumors. Additional alterations in the MAPK pathway (EGFR, KRAS among others) and in estrogen receptor transcriptional regulators (MYC, CTCF, FOXA1 and TBX3) were also more common compared to hormonal therapy-naive tumors.</p> <p>To determine whether candidate genomic lesions in the MAPK pathway and estrogen receptor transcriptional regulators were present prior to therapy or whether such lesions arose under the selective pressure of therapy, we performed whole-exome sequencing in select patients who had adequate samples acquired prior to and after progression on endocrine therapy. In total, 95 specimens corresponding to 30 treatment-naive primary tumors, 35 post-treatment tumors, and 30 normal samples were sequenced from 30 patients with endocrine-resistant metastatic breast cancer.</p>
| phs001674 | dbGaP
Project description:Estrogen receptor alpha (ERalpha) is a ligand-dependent transcription factor that plays an important role in breast cancer. Estrogen-dependent gene regulation by ERalpha can be mediated by interaction with other DNA-binding proteins, such as activator protein-1 (AP-1). The nature of such interactions in mediating the estrogen response in breast cancer cells remains unclear. Here we show that knockdown of c-Fos, a component of the transcription factor AP-1, attenuates the expression of 37% of all estrogen-regulated genes, suggesting that AP-1 is a fundamental factor for ERalpha-mediated transcription. Additionally, knockdown of c-Fos affected the expression of a number of genes that were not regulated by estrogen. Pathway analysis reveals that silencing of c-Fos downregulates an E2F1-dependent pro-proliferative gene network. Thus, modulation of the E2F1 pathway by c-Fos represents a novel mechanism by which c-Fos enhances breast cancer cell proliferation. Furthermore, we show that c-Fos and ERalpha can cooperate in regulating E2F1 gene expression by binding to regulatory elements in the E2F1 promoter. To start to dissect the molecular details of the cross-talk between AP-1 and estrogen signaling, we identify a novel ERalpha/AP-1 target, PKIB (cAMP-dependent protein kinase inhibitor-beta), which is overexpressed in ERalpha-positive breast cancer tissues. Knockdown of PKIB by siRNA results in drastic growth suppression of breast cancer cells. Collectively, our findings support AP-1 as a critical factor that governs estrogen-dependent gene expression and breast cancer proliferation programs.
2012-08-06 | GSE36586 | GEO
Project description:Altered expression of microRNAs (miRNAs), an abundant class of small non-protein-coding RNAs that mostly function as negative regulators of protein-coding gene expression, is common in cancer. Here we analyze the regulation of miRNA expression in response to estrogen, a steroid hormone that is involved in the development and progression of breast carcinomas and that is acting via the estrogen receptors (ER) transcription factors. We set out to thoroughly describe miRNA expression, by using miRNA microarrays and real time RTPCR experiments, in various breast tumor cell lines in which estrogen signaling has been induced by 17β-estradiol (E2). We show that the expression of a broad set of miRNAs decreases following E2 treatment in an ER-dependent manner. We further show that enforced expression of several of the repressed miRNAs reduces E2-dependent cell growth, thus linking expression of specific miRNAs with estrogen-dependent cellular response. In addition, a transcriptome analysis revealed that the E2-repressed miR-26a and miR-181a regulate many genes associated with cell growth and proliferation, including the progesterone receptor gene, a key actor in estrogen signaling. Strikingly, miRNA expression is also regulated in breast cancers of women who had received antiestrogen neoadjuvant therapy thereby showing an estrogen-dependent in vivo regulation of miRNA expression. Overall, our data indicates that the extensive alterations in miRNA regulation upon estrogen signalling pathway plays a key role in estrogen-dependent functions and highlights the utility of considering miRNA expression in the understanding of antiestrogen resistance of breast cancer.
2009-08-04 | GSE17460 | GEO