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Effects of LIFR inhibition using EC359 on TNBC cells in obesity conditions

ABSTRACT: In a study using syngeneic BALB/c mice, the impact of a high-fat diet (HFD) on triple-negative breast cancer (TNBC) progression was investigated using 4T1 cells. Mice were fed either a low-fat diet (LFD) or HFD for six weeks before receiving orthotopic injections of 4T1 cells. Post-tumor formation, mice were randomized into three groups: LFD, HFD, and HFD with EC359 treatment. Results indicated that HFD significantly enhanced tumor growth, while EC359 treatment notably reduced HFD-induced TNBC progression. To explore underlying mechanisms, global RNA sequencing was performed on tumor tissues, revealing that HFD altered the expression of 578 genes compared to LFD, with 325 genes differentially expressed between the HFD and HFD + EC359 groups. Gene set enrichment analysis showed that HFD-related genes were linked to cytokine signaling, inflammation, stem cell pathways, TGFβ, metastasis, and epithelial–mesenchymal transition, all of which were downregulated with EC359 treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE280092 | GEO | 2024/11/14

REPOSITORIES: GEO

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Project description:An 8-week high fat palm oil diet causes obesity and insulin resistance in C57BL/6J mice, but induces only small changes in the muscle transcriptome. Introduction: The metabolic syndrome (MS) is a cluster of metabolic abnormalities linked to an increased risk of type 2 diabetes and cardiovascular diseases. Two major characteristics of the MS are obesity and insulin resistance. In the present study we investigated the effect of obesity and insulin resistance on the mouse muscle transcriptome. Methods: C57BL/6J mice were fed a palm oil-based low fat diet (LFD) or high fat diet (HFD) for eight weeks. Microarray analysis was performed by using two complementary strategies: (1) 8-week HFD transcriptome versus 8-week LFD transcriptome and (2) transcriptome of mice sacrificed at the start of the intervention versus 8-week LFD transcriptome and 8-week HFD transcriptome, respectively. Results: HFD mice develop obesity and whole-body insulin resistance. Despite these metabolic disturbances we found that HFD induces relatively small changes in gene expression (< 1.3 fold). Only the up-regulation of FA oxidation and the down-regulation of the MAPK cascade were specific for the HFD intervention. Eight-weeks of aging induced more changed gene expression levels than the HFD, including genes involved in cell-cell interaction and development. Conclusion: Eight weeks of aging induce more pronounced changes in the muscle transcriptome than an HFD. Since only one strategy revealed the transcriptional down-regulation of the MAPK cascade, whereas both strategies showed the up-regulation of FA oxidation we suggest the use of complementary analysis strategies by the genome-wide search of gene expression changes induced by mild interventions, such as an HFD. Keywords: diet intervention and time course In this study, C57BL/6J mice were fed a high fat (HF) diet for 8 weeks to induce obesity and insulin resistance. Plasma levels of the adipokines leptin and adiponectin were measured. To investigate how these metabolic disturbances will influence the skeletal muscle transcriptome we performed whole-genome microarray analysis. Functional implications were assessed by analyses of predefined gene sets based on Gene Ontology, biochemical, metabolic and signaling pathways.

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Effects of LIFR inhibition using EC359 on TNBC cells in obesity conditions

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