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The Neuregulin 1-HER axis as a key mediator of hyperglycemic memory effects in breast cancer

ABSTRACT: Poor outcomes in diabetic patients are observed across a range of human tumors, suggesting that cancer cells develop unique characteristics under diabetic conditions. Cancer cells exposed to hyperglycemic insults acquire permanent aggressive traits of tumor growth, even after a return to euglycemic conditions. Comparative genome-wide mapping of hyperglycemia-specific open chromatin regions and concomitant mRNA expression profiling revealed that neuregulin-1 gene, an established endogenous ligand for the HER3 receptor, is activated through a putative distal enhancer. Our findings highlight the targeted inhibition of NRG1-HER3 pathways as a potential target for the treatment breast cancer patients with associated diabetes

ORGANISM(S): Mus musculus

PROVIDER: GSE40949 | GEO | 2012/09/19

SECONDARY ACCESSION(S): PRJNA175424

REPOSITORIES: GEO

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The Neuregulin 1-HER axis as a key mediator of hyperglycemic memory effects in breast cancer

Project description:Poor outcomes in diabetic patients are observed across a range of human tumors, suggesting that cancer cells develop unique characteristics under diabetic conditions. Cancer cells exposed to hyperglycemic insults acquire permanent aggressive traits of tumor growth, even after a return to euglycemic conditions. Comparative genome-wide mapping of hyperglycemia-specific open chromatin regions and concomitant mRNA expression profiling revealed that neuregulin-1 gene, an established endogenous ligand for the HER3 receptor, is activated through a putative distal enhancer. Our findings highlight the targeted inhibition of NRG1-HER3 pathways as a potential target for the treatment breast cancer patients with associated diabetes Chromatin was extracted from hyperglycemic (HyG) and euglycemic (Control) cancer cells; FAIRE DNA and input DNA from each sample were used to generate libraries for single end sequencing on the the SOLiD 4 HQ system

2012-09-19 | E-GEOD-40949 | biostudies-arrayexpress

Hyperglycemic Memory – New insights into a thought to be known topic

Project description:Hyperglycemic memory is part of the pathogenesis of diabetic retinopathy. We established a novel mouse model of intermediate-term hyperglycemic memory and demonstrated that changes in gene expression and microvascular damage in the neurovascular unit of the diabetic retina persist after euglycemic reentry, indicating memory. Using microarrays and functional annotation clustering of full genome expression data, genes meeting the criteria for hyperglycemic memory were attributed to the cytoskeletal and nuclear compartments of cells of the neurovascular unit.

2017-02-01 | GSE87433 | GEO

Gene expression in the pancreatic lymph nodes (PLN) of hyperglycemic 16-week-old Non-Obese Diabetic (NOD) mice compared to expression the PLN of euglycemic 16-week-old NOD mice.

Project description:These experiments were performed to identify differentially expressed genes in the pancreatic lymph nodes of hyperglycemic NOD mice with high levels of destructive insulitis compared to euglycemic mice with lower levels of insulitis. The pancreatic lymph nodes of 16-week-old hyperglycemic and euglycemic NOD mice were isolated and homogenized in Trizol reagent (Invitrogen). Total RNA was extracted from the aqueous phase using the RNeasy mini kit (Qiagen). RNA quality was assessed using the Agilent 2100 Bioanalyzer and the RNA 6000 Nano Reagent Kit (Agilent). Total RNA from the PLN of hyperglycemic mice (n=2) were labelled with Cy5 and run individually against a pool of Cy3-labeled total RNA isolated from euglycemic mice (n=2). Microarrays were performed using the Whole Mouse Genome Microarray Kit, 4M-CM-^W44K 2-color arrays (Agilent Technologies).

2014-06-01 | E-GEOD-57237 | biostudies-arrayexpress

Characterization of signaling pathways associated with pancreatic beta-cell adaptive flexibility in compensation of obesity-linked diabetes in db/db miceCharacterization of signaling pathways associated with pancreatic β-cell adaptive flexibility in compensation of obesity-linked diabetes in db/db mice

Project description:To characterize the signaling mechanisms underlying beta-cell dysfunction in db/db mice and their return to a more “normal” beta-cell phenotype, we applied a mass spectrometry-based quantitative phosphophoproteomics and sialiomics(sialylated N-linked glycopeptides) approach to normal and db/db beta-cells from hyperglycemic and euglycemic environments.

2020-05-19 | PXD017469 | Pride

Neuregulin 1 type III reduces severity in a mouse model of Congenital Hypomyelination Neuropathy

Project description:Purpose: We hypothesised that neuregulin 1 type III would reverse CHN. Using a faithful mouse model of CHN, we rescued the myelination defects by activation of Nrg1 type III. Unexpectedly, rescue did not depend on upregulation of Egr2 or major myelin genes. Therefore we asked whether we could identify any transcriptomic signature of the canonical pathways downstream of Nrg1 type III that could explain the increase in myelination in the sciatic nerve. Methods: Sciatic nerve mRNA profiles of 30-day-old wild-type (WT), P0 mutant (Q215X/+), trangenic HA-NRG1 type III, and HA-NRG1 type III:Q215X mice were generated by deep sequencing, in duplicate, using Illumina HiSeq2500 . The sequence reads that passed quality filters were aligned to the mouse reference genome (mm10) with the transcript annotation (UCSC mm10 annotation download from TopHat website) using TopHat (v2.0.9). Quantification for the gene expression and differential expression analysis were done by the software Cufflinks (v2.2.0). Results: A comprehensive transcriptomic analysis of signals downstream of neuregulin 1 type III in rescued CHN nerves revealed imbalanced activation of MAPK/ERK signals and minor myelin genes, such as Pmp2 and Omg. Conclusions: Our findings demonstrate that although augmented Nrg1 type III activity modifies the composition of myelin, it still promotes thicker myelin and ameliorates nerve conduction velocity in a mouse model of CHN. Controlled increase of Nrg1 type III activity may be a therapeutic strategy in some hypomyelinating neuropathies.

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Identification of Nrg1 enhancer binding proteins

Project description:Hyperglycemia is a risk factor for breast cancer-related morbidity and mortality. Hyperglycemia induces Neuregulin 1 (Nrg1) overexpression in breast cancer, which subsequently promotes tumor progression. However, molecular mechanisms underlying hyperglycemia-induced Nrg1 overexpression remain poorly understood. Here, We used DNA-protein pull-down using Nrg1 enhancer sequence as bait followed by LC/MS and identified RBPJ as a key component of the Nrg1 enhanceosome. We show that hyperglycemia causes active histone modifications at the Nrg1 enhancer, forming enhanceosome complexes where RBPJ, P300, and SETD1A are recruited to upregulate Nrg1 expression.

2023-01-29 | PXD038668 | Pride

Gene expression in the pancreatic lymph nodes (PLN) of hyperglycemic 16-week-old Non-Obese Diabetic (NOD) mice compared to expression the PLN of euglycemic 16-week-old NOD mice.

2014-06-01 | GSE57237 | GEO

Identification of Nrg1 enhancer binding proteins

2022-12-21 | MSV000090951 | MassIVE

Proteomic analysis of healthy and hyperglycemic murine fetal kidneys

Project description:Alteration of kidney morphogenesis in diabetic pregnancies is poorly described, especially changes in the extracellular matrix (ECM) and glomerular basement membrane (GBM during glomerulogenesis. Addressing the ECM proteome, or matrisome, in the mouse fetal kidney in a healthy and diabetic environment will improve understanding about the association between ECM changes in the kidney as potential reprogramming mechanisms of kidney differentiation in diabetic pregnancies. Therefore, to better understand ECM composition and remodelling in kidney developmental and appreciate the alterations associated to the maternal diabetes, this project aimed to define the matrisome in the mouse fetal kidney on embryonic day 19. For this, we used an ECM enrichment approach combined with high resolution label-free tandem mass spectrometry to define the matrisome in the fetal mouse kidney (healthy and hyperglycemic) to test the hypothesis that maternal diabetes influences ECM composition, assembly and, therefore, biology.

2021-10-13 | PXD025874 | Pride

effect of neuregulin on cardiocytes

Project description:Parallel treatment of adult rat primary cultured cardiocytes with neuregulin 1 beta or media only for 24 hours

2010-05-27 | E-GEOD-1094 | biostudies-arrayexpress