The Glucocorticoid Receptor Interferes with Progesterone Receptor-Dependent Genomic Regulation in Breast Cancer Cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA523539 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8601860.fastq.gz | Fastqsanger.gz | |||
| SRR8601870.fastq.gz | Fastqsanger.gz | |||
| SRR8601851.fastq.gz | Fastqsanger.gz | |||
| SRR8601861.fastq.gz | Fastqsanger.gz | |||
| SRR8601871.fastq.gz | Fastqsanger.gz |
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Project description:The glucocorticoid and progesterone receptors (GR and PR) are closely related members of the steroid receptor family. Despite sharing similar structural and functional characteristics; the cognate hormones display very distinct physiological responses. In mammary epithelial cells, PR activation is associated with the incidence and progression of breast cancer, whereas the GR is related to growth suppression and differentiation. Despite their pharmacological relevance, only a few studies have compared GR and PR activities in the same system. Using a PR+/GR+ breast cancer cell line, here we report that either glucocorticoid-free or dexamethasone-activated GR inhibits progestin-dependent gene expression associated to epithelial-mesenchymal-transition and cell proliferation. When both receptors are activated with their cognate hormones, PR and GR can form part of the same complex according to co-immunoprecipitation, quantitative microscopy, and sequential ChIP experiments. Moreover, genome-wide studies in cells treated with either dexamethasone or R5020, revealed the presence of several regions co-bound by both receptors. Surprisingly, GR also binds novel genomic sites in cells treated with R5020 alone. This progestin-induced GR binding was enriched in REL DNA motifs and located close to genes coding for chromatin remodelers. Understanding GR behavior in the context of progestin-dependent breast cancer could provide new targets for tumor therapy.
2019-11-25 | GSE126859 | GEO
Project description:The glucocorticoid and progesterone receptors (GR and PR) are closely related members of the steroid receptor family. Despite sharing similar structural and functional characteristics; the cognate hormones display very distinct physiological responses. In mammary epithelial cells, PR activation is associated with the incidence and progression of breast cancer, whereas the GR is related to growth suppression and differentiation. Despite their pharmacological relevance, only a few studies have compared GR and PR activities in the same system. Using a PR+/GR+ breast cancer cell line, here we report that either glucocorticoid-free or dexamethasone (DEX)-activated GR inhibits progestin-dependent gene expression associated to epithelial-mesenchymal-transition and cell proliferation. When both receptors are activated with their cognate hormones, PR and GR can form part of the same complex according to co-immunoprecipitation, quantitative microscopy and sequential ChIP experiments. Moreover, genome-wide studies in cells treated with either DEX or R5020, revealed the presence of several regions co-bound by both receptors. Surprisingly, GR also binds novel genomic sites in cells treated with R5020 alone. This progestin-induced GR binding was enriched in REL DNA motifs and located close to genes coding for chromatin remodelers. Understanding GR behavior in the context of progestin-dependent breast cancer could provide new targets for tumor therapy.
| S-EPMC6846950 | biostudies-literature
Project description:Progesterone (P) acting through its cognate nuclear receptors (PRs) plays an essential role in driving pregnancy-associated branching morphogenesis of the mammary gland. However, the fundamental mechanisms, including global cistromic and acute genomic transcriptional responses that are required to elicit active branching morphogenesis in response to P, have not been elucidated. We used microarray analysis to identify global gene expression signatures that are acutely regulated by PRs in the mouse mammary gland after acute P treatment. Mammary gland gene expression data from 10-week-old ovariectomized wildtype and progesterone receptor null mice treated subcutaneously with 17β-Estradiol for 24 hours and then 17β-Estradiol plus Progesterone for 8 or 24 hours. Three replicate pools were tested with three mice per pool.
2013-08-27 | E-GEOD-42858 | biostudies-arrayexpress
Project description:Glucocorticoids (GC) have been widely used as coadjuvants in the treatment of solid tumors, but GC treatment may be associated with poor pharmacotherapeutic response and/or prognosis. The genomic action of GC in these tumors is largely unknown. Here we find that dexamethasone (Dex, a synthetic GC) regulated genes in triple-negative breast cancer (TNBC) cells are associated with drug resistance. Importantly, these GC-regulated genes are aberrantly expressed in TNBC patients and associated with unfavorable clinical outcomes. Interestingly, in TNBC cells, Compound A (CpdA, a selective GR modulator) only regulates a small number of genes not involved in carcinogenesis and therapy resistance. Mechanistic studies using a ChIP-exo approach reveal that Dex- but not CpdA-liganded glucocorticoid receptor (GR) binds to a single glucocorticoid response element (GRE), which drives the expression of pro-tumorigenic genes. Our data suggest that development of safe coadjuvant therapy should consider the distinct genomic function between Dex- and CpdA-liganded GR. To study GR-regulated genes and define GRE in human genome, RNA-seq and GR ChIP-exo are performed in MDA-MB-231 cells before/after dex and CpdA stimulation. Each experiment includes two replicates.
2015-09-18 | E-GEOD-56022 | biostudies-arrayexpress
Project description:Tissue-specific progesterone receptor-chromatin binding and the regulation of progesterone-dependent gene expression
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Project description:Glucocorticoids (GC) have been widely used as coadjuvants in the treatment of solid tumors, but GC treatment may be associated with poor pharmacotherapeutic response and/or prognosis. The genomic action of GC in these tumors is largely unknown. Here we find that dexamethasone (Dex, a synthetic GC) regulated genes in triple-negative breast cancer (TNBC) cells are associated with drug resistance. Importantly, these GC-regulated genes are aberrantly expressed in TNBC patients and associated with unfavorable clinical outcomes. Interestingly, in TNBC cells, Compound A (CpdA, a selective GR modulator) only regulates a small number of genes not involved in carcinogenesis and therapy resistance. Mechanistic studies using a ChIP-exo approach reveal that Dex- but not CpdA-liganded glucocorticoid receptor (GR) binds to a single glucocorticoid response element (GRE), which drives the expression of pro-tumorigenic genes. Our data suggest that development of safe coadjuvant therapy should consider the distinct genomic function between Dex- and CpdA-liganded GR.
2015-09-18 | GSE56022 | GEO
Project description:Vascular inflammation is present in many cardiovascular diseases and exogenous glucocorticoids have traditionally been used as a therapy to suppress inflammation. However, recent data has shown that endogenous glucocorticoids, acting through the endothelial glucocorticoid receptor, act as negative regulators of inflammation. Here we performed chromatin immunoprecipitation for the glucocorticoid receptor followed by next-gen sequencing in mouse endothelial cells to investigate how the endothelial glucocorticoid receptor regulates vascular inflammation. We identified a novel role of the Wnt signaling pathway in this setting and show that loss of the endothelial glucocorticoid receptor results in up regulation of Wnt signaling both in vitro and in vivo using our validated mouse model. Further we demonstrate glucocorticoid receptor regulation of a key gene in the Wnt pathway via a novel glucocorticoid response element gleaned from our genomic data. These results suggest a novel role for endothelial Wnt signaling modulation in states of vascular inflammation.
2020-04-07 | GSE119091 | GEO
Project description:Vascular inflammation is present in many cardiovascular diseases and exogenous glucocorticoids have traditionally been used as a therapy to suppress inflammation. However, recent data has shown that endogenous glucocorticoids, acting through the endothelial glucocorticoid receptor, act as negative regulators of inflammation. Here we performed chromatin immunoprecipitation for the glucocorticoid receptor followed by next-gen sequencing in mouse endothelial cells to investigate how the endothelial glucocorticoid receptor regulates vascular inflammation. We identified a novel role of the Wnt signaling pathway in this setting and show that loss of the endothelial glucocorticoid receptor results in up regulation of Wnt signaling both in vitro and in vivo using our validated mouse model. Further we demonstrate glucocorticoid receptor regulation of a key gene in the Wnt pathway via a novel glucocorticoid response element gleaned from our genomic data. These results suggest a novel role for endothelial Wnt signaling modulation in states of vascular inflammation.
2020-04-07 | GSE119092 | GEO
Project description:Progesterone (P4) acting through its cognate receptor, the progesterone receptor (PR), plays an important role in uterine physiology. The PR knockout (PRKO) mouse has demonstrated the importance of the P4-PR axis in the regulation of uterine function. To define the molecular pathways regulated by P4-PR in the mouse uterus, Affymetrix MG U74Av2 oligonucleotide arrays were used to identify alterations in gene expression after acute and chronic P4 treatments. In the analysis, retinoic acid metabolic genes, cytochrome P 450 26a1 (Cyp26a1), alcohol dehydrogenase 5, and aldehyde dehydrogenase 1a1 (Aldh1a1); kallikrein genes, Klk5 and Klk6; and specific transcription factors, GATA-2 and Cited2 [cAMP-corticosterone-binding protein/p300-interacting transactivator with glutamic acid (E) and aspartic acid (D)-rich tail], were validated as regulated by the P4-PR axis. Identification and analysis of these responsive genes will help define the role of PR in regulating uterine biology. Ovariectomized wild-type and progesterone receptor knockout mice were injected with either vehicle or 1 mg/mouse progesterone. The injections were repeated every 12 h, and groups of mice were killed 4 h after the first injection (acute P4 treatment) or 4 h after the fourth injection (chronic P4 treatment).
2012-08-06 | E-GEOD-39920 | biostudies-arrayexpress
Project description:Corticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regualtion
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