Transcription profiling of estradiol treated mouse fetal urogenital sinus mesenchyme cells
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Julia Taylor
PROVIDER: E-GEOD-16854 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Developmental exposure of mouse fetuses to estrogens results in dose-dependent permanent effects on prostate morphology and function. Fetal prostatic mesenchyme cells express estrogen receptor alpha (ERα) and androgen receptors and convert stimuli from estrogens and androgens into signaling to regulate epithelial cell proliferation and differentiation. To obtain mechanistic insight into the role of different doses of estradiol (E2) in regulating mesenchymal cells, we examined E2-induced transcriptomal changes in primary cultures of fetal mouse prostate mesenchymal cells. Urogenital sinus mesenchyme cells were obtained from male mouse fetuses at gestation day 17 and exposed to 10 pM, 100 pM or 100 nM E2 in the presence of a physiological concentration of dihydrotestosterone (0.69 nM) for four days. Gene ontology studies suggested that low doses of E2 (10 pM and 100 pM) induce genes involved in cell adhesion, morphological tissue development, and sterol biosynthesis but suppress genes involved in growth factor signaling and cell adhesion. Genes showing inverted-U-shape dose responses (enhanced by E2 at 10 pM E2 but suppressed at 100 pM) were identified, and their enrichment in the glycolytic pathway was demonstrated. At the highest dose (100 nM), E2 induced genes enriched not only for cell adhesion but also steroid hormone signaling and metabolism, cytokines and their receptors, cell-to-cell communication, Wnt signaling, and TGF-β signaling. These results suggest that prostate mesenchymal cells may regulate epithelial cells through direct cell contacts when estrogen level is low whereas soluble growth factors might play significant roles when estrogen level is high. Primary culture urogenital sinus mesenchymal cells were isolated from prostate glands of gestation day 17 CD1 male mouse fetuses. Cells were then exposed to 10 pM or 100 pM 17beta-estradiol or vehicle (0.05% ethanol) for four days in the presence of 690 pM 5alpha-dihydrotestosterone. Total cellular RNA was then isolated for determination of transcriptomal profiles by Affymetrix mouse gene 1.0 ST array.
2012-03-21 | E-GEOD-36630 | biostudies-arrayexpress
Project description:Developmental estrogen exposure causes permanent alterations to mouse prostate development. Fetal prostatic mesenchyme cells regulate epithelial cell proliferation and differentiation, and alterations to mesenchymal regulation of prostate epithelial cell proliferation and differentiation may lead to permanent changes in gland structure and function. Our goal was to understand how mesenchymal cells convert estrogen signaling to stimuli that affect epithelial cells. We used microarrays to identify estrogen-induced transcriptomal changes in primary cultures of fetal mouse prostate mesenchymal cells.
2009-06-27 | GSE16854 | GEO
Project description:Three quarters of all breast cancer cases express the estrogen receptor (ER, ESR1 gene), which promotes tumor growth and constitutes a direct target for endocrine therapies. ESR1 mutations have been implicated in therapy resistance in metastatic breast cancers, in particular to aromatase inhibitors. ESR1 mutations promote constitutive ER activity and affect other signaling pathways, allowing cancer cells to proliferate by employing mechanisms within and outwith direct regulation by the ER. Although subjected to extensive genetic and transcriptomic analyses, understanding of protein alterations remains poorly investigated. Towards this, we employed an integrated mass spectrometry (MS) based proteomic approach to profile the protein and phosphoprotein differences in breast cancer cell lines expressing the frequent Y537N and Y537S ER mutations. Global proteome analysis revealed enrichment of mitotic and immune signaling pathways in ER mutant cells, while phosphoprotein analysis evidenced enriched activity of proliferation associated kinases, in particular CDKs and MTOR. Integration of protein expression and phosphorylation data revealed pathway-dependent discrepancies (motility vs proliferation) that were observed at varying degrees across mutant and wt ER cells. Additionally, protein expression and phosphorylation patterns, while under different regulation, still recapitulated the estrogen-independent phenotype of ER mutant cells.
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Project description:Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. Recent studies have demonstrated that in addition to its role in promoting proliferation, ERα also protects tumors against metastatic transformation. Current therapeutics antagonize ERα and interfere with both beneficial and detrimental signaling pathways stimulated by ERα. The goal of this study is to uncover the dynamics of coding and non-coding RNA (microRNA) expression in response to estrogen stimulation and identify potential therapeutic targets that more specifically inhibit ERα-stimulated growth and survival pathways without interfering with its protective features. To achieve this, we exposed MCF7 cells (an estrogen receptor positive model cell line for breast cancer) to estrogen and prepared a time course of paired mRNA and miRNA sequencing libraries at ten time points throughout the first 24 hours of the response to estrogen. From these data, we identified three primary expression trendsâ??transient, induced, and repressedâ??that were each enriched for genes with distinct cellular functions. Integrative analysis of paired mRNA and microRNA temporal expression profiles identified miR-503 as the strongest candidate master regulator of the estrogen response, in part through suppression of ZNF217â??an oncogene that is frequently amplified in cancer. We confirmed experimentally that miR-503 directly targets ZNF217 and that over-expression of miR-503 suppresses breast cancer cell proliferation. Overall, these data indicate that miR-503 acts as a potent estrogen-induced tumor suppressor microRNA that opposes cellular proliferation and has promise as a therapeutic for breast cancer. More generally, our work provides a systems-level framework for identifying functional interactions that shape the temporal dynamics of gene expression. Quantification of miRNAs in MCF7 cells responding to estrogen following a period of estrogen starvation. Three independent biological replicates (30 samples: 3 replicates x 10 time points) of MCF7 cells were exposed to 10nM Estradiol for 0, 1, 2, 3, 4, 5, 6, 8, 12 , or 24 hours, and total RNA was extracted from the samples. Total RNA was used to generate paired RNA and miRNA sequencing. The miRNA libraries were prepared using the Bioo Scientific NextFLEX v2 library preparation kit.
2016-08-19 | E-GEOD-78168 | biostudies-arrayexpress
Project description:Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. Recent studies have demonstrated that in addition to its role in promoting proliferation, ERα also protects tumors against metastatic transformation. Current therapeutics antagonize ERα and interfere with both beneficial and detrimental signaling pathways stimulated by ERα. The goal of this study is to uncover the dynamics of coding and non-coding RNA (microRNA) expression in response to estrogen stimulation and identify potential therapeutic targets that more specifically inhibit ERα-stimulated growth and survival pathways without interfering with its protective features. To achieve this, we exposed MCF7 cells (an estrogen receptor positive model cell line for breast cancer) to estrogen and prepared a time course of paired mRNA and miRNA sequencing libraries at ten time points throughout the first 24 hours of the response to estrogen. From these data, we identified three primary expression trendsâ??transient, induced, and repressedâ??that were each enriched for genes with distinct cellular functions. Integrative analysis of paired mRNA and microRNA temporal expression profiles identified miR-503 as the strongest candidate master regulator of the estrogen response, in part through suppression of ZNF217â??an oncogene that is frequently amplified in cancer. We confirmed experimentally that miR-503 directly targets ZNF217 and that over-expression of miR-503 suppresses breast cancer cell proliferation. Overall, these data indicate that miR-503 acts as a potent estrogen-induced tumor suppressor microRNA that opposes cellular proliferation and has promise as a therapeutic for breast cancer. More generally, our work provides a systems-level framework for identifying functional interactions that shape the temporal dynamics of gene expression. Quantification of mRNAs in MCF7 cells responding to estrogen following a period of estrogen starvation. Three independent biological replicates (30 samples: 3 replicates x 10 time points) of MCF7 cells were exposed to 10nM Estradiol for 0, 1, 2, 3, 4, 5, 6, 8, 12 , or 24 hours, and total RNA was extracted from the samples. Total RNA was used to generate paired RNA and miRNA sequencing. RNA libraries were prepared using an Illumina TruSeq stranded mRNA library preparation kit.
2016-08-19 | E-GEOD-78167 | biostudies-arrayexpress
Project description:We developed Chromatin Interaction Analysis by Paired-End Tag sequencing (ChIA-PET) for de novo detection of global chromatin interactions, and comprehensively mapped the chromatin interaction network bound by estrogen receptor α (ERα) in the human genome. We performed 454 and Illumina sequencing analyses. Keywords: Epigenetics Using 454, we examined 3 libraries: IHM001 (Estrogen Receptor ChIA-PET), IHM043 (Estrogen Receptor ChIP-PET) and IHM062 (IgG ChIA-PET) Using Illumina, we examined 4 libraries: IHM001 (Estrogen Receptor ChIA-PET replicate 1, Paired End Sequencing), IHH015 (Estrogen Receptor ChIA-PET replicate 2, Paired End Sequencing), H3K4me3 ChIP-Seq and RNA polymerase II ChIP-Seq
2009-09-11 | E-GEOD-18046 | biostudies-arrayexpress
Project description:Estrogen receptor-α (ERα) is an important driver of breast cancer and is the target for hormonal therapies, anti-estrogens and drugs that limit estrogen biosynthesis (aromatase inhibitors). Mutations in the ESR1 gene identified in metastatic breast cancer provide a potential mechanism for acquired resistance to hormone therapies. We have used CRISPR-Cas9 mediated genome editing in the MCF-7 breast cancer cell line, generating MCF-7-Y537S. MCF-7-Y537S cells encode a wild-type (tyrosine 537) and a mutant (serine 537) allele. Growth of the line is estrogen-independent and expression of ERα target genes is elevated in the absence of estrogen. ER ChIP-seq was carried out to map global ERα binding sites in the presence and absence of estrogen. RNA-seq following estrogen treatment was used for gene expression analysis. We show that expression of ER target genes and ER recruitment to ER binding regions is similar in MCF-7 and MCF-7-Y537S cells, except that ER recruitment to DNA and expression of ER target genes is frequently elevated in the absence of estrogen. Hormone depleted MCF7 Luc or Y537S cells were treated with 10nM E2 or ethanol, as vehicle control, for 8 hours, with 3 replicates (2 replicates for Y537S + E2). RNA-seq was carried out using Illumina Hiseq 2500.
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Project description:Two subtypes of the estrogen receptor, ERalpha and ERbeta, mediate the actions of estrogens, and the majority of human breast tumors contain both ERalpha and ERbeta. To examine the possible interactions and modulatory effects of ERbeta on ERalpha activity, we have used adenoviral gene delivery to produce human breast cancer (MCF-7) cells expressing ERbeta, along with their endogenous ERalpha. We have examined the effects of ERβ expression on genome-wide gene expression by Affymetrix GeneChip microarrays. We find that ERbeta modulated estrogen gene expression on nearly 24% of E2-stimulated genes but only 8% of E2-inhibited genes. We find that ERbeta modulation is gene-specific, enhancing or counteracting ERalpha regulation for distinct subsets of estrogen target genes. Introduction of ERbeta into ERalpha-containing cells induced up/down-regulation of many estrogen target in the absence of any added ligand. In addition, ERbeta presence elicited the expression of a unique set of genes that were not regulated by ERalpha alone. ERbeta modulated the expression of genes in many functional categories, but the greatest numbers were associated with transcription factor and signal transduction pathways. Regulation of multiple components in the TGF beta, SDF1, and semaphorin pathways, may contribute to the suppression of proliferation observed with ERbeta both in the presence and absence of estrogen. Hence, ERbeta modulates ERalpha gene regulation in diverse ways that may contribute to its growth-inhibiting beneficial effects in breast cancer Experiment Overall Design: MCF-7 cells expressing endogenous ERalpha were infected with adenovirus carrying either estrogen receptor beta (AdERb) or no insert (Ad) at multiplicity of infection (moi) of 5 or 50. Cells were infected with adenovirus for a period of 48hr before treatment with ligand (vehicle control or 10nM 17beta-estradiol) for a additional period of 24hr before harvest.
2009-04-24 | E-GEOD-4006 | biostudies-arrayexpress
Project description:The beneficial effect of the selective estrogen receptor (ER) modulator tamoxifen in the treatment and prevention of breast cancer is assumed to be through its ability to antagonize the stimulatory actions of estrogen, although tamoxifen can also have some estrogen-like agonist effects. Here, we report that, in addition to these mixed agonist/antagonist actions, tamoxifen can also selectively regulate a unique set of >60 genes, which are minimally regulated by estradiol (E2) or raloxifene in ERalpha-positive MCF-7 human breast cancer cells. This gene regulation by tamoxifen is mediated by ERalpha and reversed by E2 or ICI 182,780. Introduction of ERbeta into MCF-7 cells reverses tamoxifen action on approximately 75% of these genes. To examine whether these genes might serve as markers of tamoxifen sensitivity and/or the development of resistance, their expression level was examined in breast cancers of women who had received adjuvant therapy with tamoxifen. High expression of two of the tamoxifen-stimulated genes, YWHAZ/14-3-3z and LOC441453, was found to correlate significantly with disease recurrence following tamoxifen treatment in women with ER-positive cancers and hence seem to be markers of a poor prognosis. Our data indicate a new dimension in tamoxifen action, involving gene expression regulation that is tamoxifen preferential, and identify genes that might serve as markers of tumor responsiveness or resistance to tamoxifen therapy. This may have a potential effect on the choice of tamoxifen versus aromatase inhibitors as adjuvant endocrine therapy.
2007-10-02 | E-GEOD-4025 | biostudies-arrayexpress
Project description:Three quarters of all breast cancer cases express the estrogen receptor (ER, ESR1 gene), which promotes tumor growth and constitutes a direct target for endocrine therapies. ESR1 mutations have been implicated in therapy resistance in metastatic breast cancers, in particular to aromatase inhibitors. ESR1 mutations promote constitutive ER activity and affect other signaling pathways, allowing cancer cells to proliferate by employing mechanisms within and outwith direct regulation by the ER. Although subjected to extensive genetic and transcriptomic analyses, understanding of protein alterations remains poorly investigated. Towards this, we employed an integrated mass spectrometry (MS) based proteomic approach to profile the protein and phosphoprotein differences in breast cancer cell lines expressing the frequent Y537N and Y537S ER mutations. Global proteome analysis revealed enrichment of mitotic and immune signaling pathways in ER mutant cells, while phosphoprotein analysis evidenced enriched activity of proliferation associated kinases, in particular CDKs and MTOR. Integration of protein expression and phosphorylation data revealed pathway-dependent discrepancies (motility vs proliferation) that were observed at varying degrees across mutant and wt ER cells. Additionally, protein expression and phosphorylation patterns, while under different regulation, still recapitulated the estrogen-independent phenotype of ER mutant cells.
2024-03-26 | PXD032285 | Pride