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A tumor suppressive relationship between mineralocorticoid and retinoic receptors activates a transcriptional program consistent with a reverse Warburg effect in breast cancer

ABSTRACT: Whole transcriptome profiling in MR inducible MCF-7 cells after combinations of ligand treatments

ORGANISM(S): Homo sapiens

PROVIDER: GSE160497 | GEO | 2020/10/31

REPOSITORIES: GEO

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A tumour suppressive relationship between mineralocorticoid and retinoic acid receptors activates a transcriptional program consistent with a reverse Warburg effect in breast cancer.

Project description:BackgroundThe role of nuclear receptors in both the aetiology and treatment of breast cancer is exemplified by the use of the oestrogen receptor (ER) as a prognostic marker and treatment target. Treatments targeting the oestrogen signalling pathway are initially highly effective for most patients. However, for the breast cancers that fail to respond, or become resistant, to current endocrine treatments, the long-term outlook is poor. ER is a member of the nuclear receptor superfamily, comprising 48 members in the human, many of which are expressed in the breast and could be used as alternative targets in cases where current treatments are ineffective.MethodsWe used sparse canonical correlation analysis to interrogate potential novel nuclear receptor expression relationships in normal breast and breast cancer. These were further explored using whole transcriptome profiling in breast cancer cells after combinations of ligand treatments.ResultsUsing this approach, we discovered a tumour suppressive relationship between the mineralocorticoid receptor (MR) and retinoic acid receptors (RAR), in particular RARβ. Expression profiling of MR expressing breast cancer cells revealed that mineralocorticoid and retinoid co-treatment activated an expression program consistent with a reverse Warburg effect and growth inhibition, which was not observed with either ligand alone. Moreover, high expression of both MR and RARB was associated with improved breast cancer-specific survival.ConclusionOur study reveals a previously unknown relationship between MR and RAR in the breast, which is dependent on menopausal state and altered in malignancy. This finding identifies potential new targets for the treatment of breast cancers that are refractory to existing therapeutic options.

| S-EPMC7641839 | biostudies-literature

A tumor suppressive relationship between mineralocorticoid and retinoic receptors activates a transcriptional program consistent with a reverse Warburg effect in breast cancer

Project description:A tumor suppressive relationship between mineralocorticoid and retinoic receptors activates a transcriptional program consistent with a reverse Warburg effect in breast cancer

| PRJNA673399 | ENA

ChIP-nexus of mineralocorticoid receptors and glucocorticoid receptors in neuroblastoma cells

Project description:Purpose: To compare the binding profiles of mineralocorticoid and glucocorticoid receptors after corticosterone treatment in neuroblastoma cells. Methods: Tagged glucocorticoid receptors (eGFP-rat GR) and mineralocorticoid receptors (mCherry-rat MR) were transiently transfected into Neuro2A mouse neuroblastoma cells and treated with (i) vehicle, (ii) corticosterone 100 nM for 20 mins and (iii) corticosterone 100 nM for 20 mins followed by media repacement twice and 40 mins further incubation in charcoal-stripped serum media. ChIP-nexus samples were prepared in triplicate for deep sequencing using Illumina NextSeq, as well as control samples taken from cell lysates before immunoprecipitation. Sequence data was analyzed and processed for the identification of enriched binding sites, using MACS2, and for the characteristic staggered ChIP-nexus borders, using the MACE pipeline (Wang et al., 2014). Results: Corticosterone-sensitive glucocorticoid receptor (GR) binding sites and mineralocorticoid receptor (MR) binding sites showed considerable overlap, by MACS2 analysis. GR and MR binding sites were highly similar showing recruitment to the same DNA sites, by MACE analysis (Wang et al., 2014). Further analyses showed GR could tether MR to the DNA by GR in a functional manner such that gene expression could be altered by the presence of tethered MR. Conclusions: MR can be recruited to DNA-binding sites by GR, even in the absence of MR DNA-binding. MR can interact in multiple modes at genomic DNA binding sites.

2019-03-15 | GSE115417 | GEO

Exploiting crosstalk between glucocorticoid and mineralocorticoid receptors enhances glucocorticoid-induced killing of multiple myeloma cells

Project description:Long-term glucocorticoid treatment in multiple myeloma is hampered by deleterious side effects. Glucocorticoids bind to the glucocorticoid receptor (GR), which is a crucial drug target because its activation triggers myeloma cell death. The mineralocorticoid receptor (MR) is a closely related nuclear receptor but its impact on glucocorticoid responsiveness in myeloma is unknown. Here we reveal a functional crosstalk between GR and MR that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone enhances Dex-induced cell killing in (primary) myeloma cells. The crosstalk is further evidenced by an endogenous interaction between GR and MR in myeloma cells that is ligand-inducible and by a distinctive gene expression profile. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma and presents a glucocorticoid-based dose-reduction strategy that could diminish glucocorticoid-related side effects in patients.

2023-08-23 | GSE200313 | GEO

Molecular signature of mineralocorticoid signalling in cardiomyocytes

Project description:Gene expression analysis of hearts from double transgenic mice with conditional, cardiomyocyte-specific, overexpression of the mineralocorticoid (MR) or of the glucocorticoid receptor (GR). GR-mice vs controls, MR-mice vs controls. GR: 3 sample pools hybridized to 2 microarrays each. MR: 1 sample pool hybridized to 3 microarrays. Microarray contains triplicate spots.

2010-06-18 | E-GEOD-20525 | biostudies-arrayexpress

Smooth muscle cell mineralocorticoid receptor regulation of vascular microRNAs with aging

Project description:We used a smooth muscle cell-specific mineralocorticoid receptor knockout mouse to generate young and aged MR-intact and SMC-MR-KO aortic miRNA to examine the effect of age on vascular miRNA alterations in the presence and absence of SMC-MR. For more information about the mouse model see: McCurley, A et al. Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat Med. 2012 Sep;18(9):1429-33 Total miRNA was extracted from young (3-4 mo) and aged male (12mo) MR-intact and SMC-MR-KO mice to investigate aging-induced alterations in vascular miRNA expression

2016-07-29 | E-GEOD-84960 | biostudies-arrayexpress

Cistrome of the Aldosterone-activated Mineralocorticoid Receptor in Human Renal Cells

Project description:Aldosterone, the main mineralocorticoid hormone in Humans, has a major role in maintaining the hemo-electrolytique homeostasis, by acting in the distal part of nephron. This steroid hormone mainly acts through its binding to a ligand-induced transcription factor, the mineralocorticoid receptor (MR). MR binds to specific genomic sequences, where it recruits transcriptional coregulators, to activate or repress target gene transcription. The aim of this work was to access the whole aldosterone-dependand MR target genes, by comparing sequenced data from aldosterone or vehicle-treated samples. Anti-MR ChIP-seq in Human Kidney GFP-hMR cells treated with vehicle or Aldosterone.

2015-06-12 | E-GEOD-69777 | biostudies-arrayexpress

Crosstalk between the glucocorticoid and mineralocorticoid receptor boosts glucocorticoid-induced killing of multiple myeloma cells

Project description:The glucocorticoid receptor (GR) is a crucial drug target in multiple myeloma as its activation with glucocorticoids effectively triggers myeloma cell death. However, as high-dose glucocorticoids are also associated with deleterious side effects, novel approaches are urgently needed to improve GR’s action in myeloma. Here we reveal a functional crosstalk between GR and the mineralocorticoid receptor (MR) that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone (Spi) enhances Dex-induced cell killing in primary, newly diagnosed GC-sensitive myeloma cells, while in a relapsed GC-resistant setting, Spi alone induces distinct myeloma cell killing. On a mechanistic level, we find that a GR-MR crosstalk is arising from an endogenous interaction between GR and MR in myeloma cells. Quantitative dimerization assays show that Spi reduces Dex-induced GR-MR heterodimerization and completely abolishes Dex-induced MR MR homodimerization but leaves GR-GR homodimerization intact. Unbiased transcriptomics further reveals that c-myc and many of its target genes are downregulated most by Dex and Spi combined, while proteomics analyses identify that several metabolic hallmarks are modulated most by this combination treatment. Finally, we identified a subset of Dex+Spi downregulated genes and proteins that may predict prognosis in the CoMMpass patient cohort. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma as it provides novel strategies towards glucocorticoid-based dose-reduction.

2023-10-24 | PXD043635 | Pride

Aldosterone-inducible genes in mineralocorticoid receptor expressed human endothelial cell lines

Project description:To elucidate the aldosterone-regulated genes in vascular endothelial cells, we developed human endothelial cell line (EAhy926) stably expressing human mineralocorticoid receptor by retroviral system (MR-EAhy). Then gene expression profile of MR-EAhy stimulated with or without aldosterone was compared using DNA microarray analysis. MR-EAhy were serum-deprived for 24h with 0.2% dextran-coated charcoal-treated FBS, and then stimulated with or without aldosterone (10-9 M) for 6 hr. Then cells were harvested for RNA extraction.

2011-03-18 | E-GEOD-28009 | biostudies-arrayexpress

Smooth muscle cell mineralocorticoid receptor regulation of vascular mRNAs with aging

Project description:We used a smooth muscle cell-specific mineralocorticoid receptor knockout mouse to generate young and aged MR-intact and SMC-MR-KO aortic mRNA to examine the effect of age on vascular mRNA alterations in the presence and absence of SMC-MR. For more information about the mouse model see: McCurley, A et al. Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat Med. 2012 Sep;18(9):1429-33

2017-08-10 | GSE102397 | GEO

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