Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA301974 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2921060.fastq.gz | Fastqsanger.gz | |||
| SRR2921061.fastq.gz | Fastqsanger.gz | |||
| SRR2921062.fastq.gz | Fastqsanger.gz | |||
| SRR2921062_1.fastq.gz | Fastqsanger.gz | |||
| SRR2921062_2.fastq.gz | Fastqsanger.gz |
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Project description:Approximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit estrogen receptor signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the up-regulation of alternative growth signals. The mechanisms that drive this resistance - especially epigenetic events that alter gene expression - are however not well understood. Here we performed a genome-wide DNA methylation and expression analysis of cell line models to find epigenetically regulated genes involved in acquired aromatase inhibitor resistance. We discovered that prostaglandin E2 receptor 4 (PTGER4) is up-regulated after demethylation and promotes phosphorylation and activation of ERα. Knockdown and inhibitor studies demonstrate that PTGER4 promotes AI resistance via ligand independent activation of the ERα-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI resistant cancers. Additionally, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and/or treatments can improve AI resistant breast cancer treatment.
2017-06-19 | GSE74941 | GEO
Project description:Approximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit estrogen receptor signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the up-regulation of alternative growth signals. The mechanisms that drive this resistance—especially epigenetic events that alter gene expression—are however not well understood. Here we performed a genome-wide DNA methylation and expression analysis of cell line models to find epigenetically regulated genes involved in acquired aromatase inhibitor resistance. We discovered that prostaglandin E2 receptor 4 (PTGER4) is up-regulated after demethylation and promotes phosphorylation and activation of ERα. Knockdown and inhibitor studies demonstrate that PTGER4 promotes AI resistance via ligand independent activation of the ERα-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI resistant cancers. Additionally, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and/or treatments can improve AI resistant breast cancer treatment.
2017-06-19 | GSE74942 | GEO
Project description:A persistent and non-resolving inflammatory response to accumulating A? peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating A? peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many pro-inflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing A?-induced inflammation represent a relatively unexplored area. Here we hypothesized that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to A?42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of A?42-induced inflammatory factors and potentiated phagocytosis of A?42. Microarray analysis was performed and demonstrated that EP4 stimulation broadly opposed A?42-driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-?B transcription factors. Primary microglia were isolated from the brains of postnatal day 7 C57BL/6J mouse pups using the Neural Tissue Dissociation Kit (P), MACS Separation Columns (LS), and magnetic CD11b Microbeads from Miltenyi Biotec (Auburn, CA). Microglia from three separate litters of pups were maintained as three independent biological replicates for each treatment. After being cultured for three days, microglia were treated with oligomeric A?42 (10uM) and/or the specific EP4 agonist AE1-329 (100nM) for 6 hours. These 4 treatment conditions (A? + AE1, A? alone, AE1 alone, and vehicle alone) and 3 independent biological replicates per treatment gave us 12 total samples. After 6 hours of treatment, RNA was isolated from the microglia for microarray analysis.
2014-04-25 | E-GEOD-55627 | biostudies-arrayexpress
Project description:A persistent and non-resolving inflammatory response to accumulating Aβ peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating Aβ peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many pro-inflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing Aβ-induced inflammation represent a relatively unexplored area. Here we hypothesized that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to Aβ42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of Aβ42-induced inflammatory factors and potentiated phagocytosis of Aβ42. Microarray analysis was performed and demonstrated that EP4 stimulation broadly opposed Aβ42-driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-κB transcription factors.
2014-04-25 | GSE55627 | GEO
Project description:Changes of genome-wide mRNA transcription levels of human ciliary smooth muscle (hCSM) cells were determined by treating hCSM cells in culture with 200 nM of either an prostaglandin E2 receptor subtype EP2 or subtype EP4 selective agonist for 6 hours in comparison to untreated controls. This was followed by competitive hybridization of fluorescent Cy3 or Cy5 labeled cRNA probes derived from the treated versus untreated control total RNA samples onto an Agilent Human Whole Genome Expression oligonucleotide microarray. Log 2 (LN) of the intra-slide ratios (RATIO, PRE_VALUE) of treated versus untreated samples was reported as VALUE in the sample files. Keywords: prostaglandin E2 receptor agonists, subtype EP2, subtype EP4, hCSM
2008-02-24 | GSE10621 | GEO
Project description:Approximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit ER signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the upregulation of alternative growth signals. The mechanisms that drive this resistance-especially epigenetic events that alter gene expression-are, however, not well understood. Genome-wide DNA methylation and expression analysis of cell line models of acquired AI resistance indicated that prostaglandin E2 receptor 4 (PTGER4) is upregulated after demethylation in resistant cells. Knockdown and inhibitor studies demonstrate that PTGER4 is essential for estrogen-independent growth. Our exploratory analysis of downstream signaling indicates that PTGER4 likely promotes AI resistance via ligand-independent activation of the ERα-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI-resistant cancers. In addition, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and treatments can improve AI-resistant breast cancer treatment.
| S-EPMC5398938 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-06-19 | GSE74943 | GEO
Project description:Foxp3+ regulatory T cells (Tregs) heavily infiltrate malignant tumors and restrict anti-tumor immunity. These tumor-infiltrating Tregs (TI-Tregs) adopt a distinct phenotype by expressing a unique set of genes including those encoding various co-stimulatory and co-inhibitory molecules. This TI-Treg gene expression signature is conserved in TI-Tregs across species and the types and stages of tumors, suggesting the presence of a common inducing mechanism or mechanisms in tumor microenvironment (TME). However, identity of such a mechanism remains elusive. Here, we show that prostaglandin E2 (PGE2) produced in TME directly acts on its receptor EP2/EP4 on Tregs to induce the TI-Treg phenotype. Indeed, PGE2 added to TCR-activated Tregs induces a set of genes, many of which are included in the reported TI-Treg signature genes, in both induced Tregs (iTregs) and naturally occurring Tregs (nTregs), in a manner dependent on EP2 and EP4 via cAMP-PKA pathway. This is not limited to phenotypic changes, as EP4 agonist-treated Tregs exhibit potent suppressive activity to CD8+ T cells and strongly inhibit their proliferation and survival. Consistently, selective loss of EP2 and EP4 in mouse Tregs and pharmacological inhibition of EP2 and EP4 reduce expression of those genes in Tregs infiltrating LLC1 mouse syngeneic tumor, and significantly delay the tumor progression. In human FOXP3+iTregs, the expression of Treg signature genes, FOXP3, CD25 and CTLA4 as well as a typical TI-Treg signature gene, 4-1BB are significantly upregulated by PGE2-EP4 signaling. Furthermore, analysis of scRNA-seq of nasopharyngeal cancer patients demonstrates preferential expression of the TI-Treg signature genes in Tregs infiltrating the PTGShi tumor group compared to the PTGS2lo tumor group. These findings suggest that PGE2-EP2/EP4 signaling is one of the molecular mechanisms inducing the TI-Treg phenotype in TME.
2025-11-24 | GSE282089 | GEO
Project description:Foxp3+ regulatory T cells (Tregs) heavily infiltrate malignant tumors and restrict anti-tumor immunity. These tumor-infiltrating Tregs (TI-Tregs) adopt a distinct phenotype by expressing a unique set of genes including those encoding various co-stimulatory and co-inhibitory molecules. This TI-Treg gene expression signature is conserved in TI-Tregs across species and the types and stages of tumors, suggesting the presence of a common inducing mechanism or mechanisms in tumor microenvironment (TME). However, identity of such a mechanism remains elusive. Here, we show that prostaglandin E2 (PGE2) produced in TME directly acts on its receptor EP2/EP4 on Tregs to induce the TI-Treg phenotype. Indeed, PGE2 added to TCR-activated Tregs induces a set of genes, many of which are included in the reported TI-Treg signature genes, in both induced Tregs (iTregs) and naturally occurring Tregs (nTregs), in a manner dependent on EP2 and EP4 via cAMP-PKA pathway. This is not limited to phenotypic changes, as EP4 agonist-treated Tregs exhibit potent suppressive activity to CD8+ T cells and strongly inhibit their proliferation and survival. Consistently, selective loss of EP2 and EP4 in mouse Tregs and pharmacological inhibition of EP2 and EP4 reduce expression of those genes in Tregs infiltrating LLC1 mouse syngeneic tumor, and significantly delay the tumor progression. In human FOXP3+iTregs, the expression of Treg signature genes, FOXP3, CD25 and CTLA4 as well as a typical TI-Treg signature gene, 4-1BB are significantly upregulated by PGE2-EP4 signaling. Furthermore, analysis of scRNA-seq of nasopharyngeal cancer patients demonstrates preferential expression of the TI-Treg signature genes in Tregs infiltrating the PTGS2hi tumor group compared to the PTGS2lo tumor group. These findings suggest that PGE2-EP2/EP4 signaling is one of the molecular mechanisms inducing the TI-Treg phenotype in TME.
2025-11-28 | GSE282088 | GEO
Project description:Foxp3+ regulatory T cells (Tregs) heavily infiltrate malignant tumors and restrict anti-tumor immunity. These tumor-infiltrating Tregs (TI-Tregs) adopt a distinct phenotype by expressing a unique set of genes including those encoding various co-stimulatory and co-inhibitory molecules. This TI-Treg gene expression signature is conserved in TI-Tregs across species and the types and stages of tumors, suggesting the presence of a common inducing mechanism or mechanisms in tumor microenvironment (TME). However, identity of such a mechanism remains elusive. Here, we show that prostaglandin E2 (PGE2) produced in TME directly acts on its receptor EP2/EP4 on Tregs to induce the TI-Treg phenotype. Indeed, PGE2 added to TCR-activated Tregs induces a set of genes, many of which are included in the reported TI-Treg signature genes, in both induced Tregs (iTregs) and naturally occurring Tregs (nTregs), in a manner dependent on EP2 and EP4 via cAMP-PKA pathway. This is not limited to phenotypic changes, as EP4 agonist-treated Tregs exhibit potent suppressive activity to CD8+ T cells and strongly inhibit their proliferation and survival. Consistently, selective loss of EP2 and EP4 in mouse Tregs and pharmacological inhibition of EP2 and EP4 reduce expression of those genes in Tregs infiltrating LLC1 mouse syngeneic tumor, and significantly delay the tumor progression. In human FOXP3+iTregs, the expression of Treg signature genes, FOXP3, CD25 and CTLA4 as well as a typical TI-Treg signature gene, 4-1BB are significantly upregulated by PGE2-EP4 signaling. Furthermore, analysis of scRNA-seq of nasopharyngeal cancer patients demonstrates preferential expression of the TI-Treg signature genes in Tregs infiltrating the PTGS2hi tumor group compared to the PTGS2lo tumor group. These findings suggest that PGE2-EP2/EP4 signaling is one of the molecular mechanisms inducing the TI-Treg phenotype in TME.
2025-11-28 | GSE282087 | GEO