The highly specific role of the insulin receptor in breast cancer progression
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE57139 | GEO | 2014/06/01
SECONDARY ACCESSION(S): PRJNA245548
REPOSITORIES: GEO
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Project description:In order to investigate insulin effect on cancer cells transcripts we stimulated the mouse mammary cancer cell line, Mvt-1 with insulin. RNA samples were extracted from Mvt-1 cells following 10nM insulin treatment for 90min and from control cells (vehicle)
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Project description:Accumulating evidence from clinical trials indicates that specific targeting of the IGF1 receptor (IGF1R) is not efficient as an anti-breast cancer treatment. One possible reason is that the mitogenic signals from the insulin receptor (IR) can be processed independently or as compensation to inhibition of the IGF1R. In this study, we highlight the role of the IR in mediating breast tumor progression in both WT mice and a hyperinsulinemic MKR mouse model by induction of Ir (Insr) or Igf1r knockdown (KD) in the mammary carcinoma Mvt-1 cell line. By using the specific IR antagonist-S961, we demonstrated that Igf1r-KD induces elevated responses by the IR to IGF1. On the other hand, Ir-KD cells generated significantly smaller tumors in the mammary fat pads of both WT and MKR mice, as opposed to control cells, whereas the Igf1r-KD cells did not. The tumorigenic effects of insulin on the Mvt-1 cells were also demonstrated using microarray analysis, which indicates alteration of genes and signaling pathways involved in proliferation, the cell cycle, and apoptosis following insulin stimulation. In addition, the correlation between IR and the potential prognostic marker for aggressive breast cancer, CD24, was examined in the Ir-KD cells. Fluorescence-activated cell sorting (FACS) analysis revealed more than 60% reduction in CD24 expression in the Ir-KD cells when compared with the control cells. Our results also indicate that CD24-expressing cells can restore, at least in part, the tumorigenic capacity of Ir-KD cells. Taken together, our results highlight the mitogenic role of the IR in mammary tumor progression with a direct link to CD24 expression.
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Project description:Insulin resistance is central to diabetes and metabolic syndrome. To define the consequences of genetic insulin resistance distinct from those secondary to cellular differentiation or in vivo regulation, we generated induced pluripotent stem cells (iPSCs) from individuals with insulin receptor mutations and age-appropriate control subjects and studied insulin signaling and gene expression compared with the fibroblasts from which they were derived. iPSCs from patients with genetic insulin resistance exhibited altered insulin signaling, paralleling that seen in the original fibroblasts. Insulin-stimulated expression of immediate early genes and proliferation were also potently reduced in insulin resistant iPSCs. Global gene expression analysis revealed marked differences in both insulin-resistant iPSCs and corresponding fibroblasts compared with control iPSCs and fibroblasts. Patterns of gene expression in patients with genetic insulin resistance were particularly distinct in the two cell types, indicating dependence on not only receptor activity but also the cellular context of the mutant insulin receptor. Thus, iPSCs provide a novel approach to define effects of genetically determined insulin resistance. This study demonstrates that effects of insulin resistance on gene expression are modified by cellular context and differentiation state. Moreover, altered insulin receptor signaling and insulin resistance can modify proliferation and function of pluripotent stem cell populations. To investigate the impact of genetic insulin resistance on transcriptional regulation in iPSCs, we analyzed global gene expression using microarrays in both fibroblasts and iPSCs.
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Project description:Hyperinsulinemia is often viewed as compensatory to insulin resistance, but studies have shown that high levels of insulin may contribute to insulin resistance. The precise mechanisms by which hyperinsulinemia contributes to insulin resistance remain poorly defined. To understand direct effects of prolonged exposure to excess insulin in muscle cells, we incubated differentiated C2C12 myotubes with elevated insulin for 16 hours, followed by 6 hours serum starvation, before examining key insulin signaling nodes. Using this model, we found that prolonged high insulin treatment significantly increased the phosphorylation of insulin receptor (INSR) and AKT, but not ERK. After starvation, acute AKT and ERK signaling stimulated by 0.2 - 20 nM insulin was attenuated. INSR protein was significantly downregulated by hyperinsulinemia in a insulin-dose-dependent manner. Surface INSR was reduced proportionally to total INSR levels. Mechanistically, we found that hyperinsulinemia strongly downregulated Insr mRNA, which was correlated with increased threonine 24 phosphorylation of FOXO1. Interestingly, 6h starvation reversed the effects of high insulin on basal phosphorylation of INSR, AKT and FOXO1, and Insr transcription. Using RNAseq, bioinformatics, and follow-up RNAi studies, we identified SIN3A as a negative regulator of Insr mRNA levels and JUND, MAX and MXI as positive regulators of Irs2 mRNA. We validated our in vitro results by determining that INSR levels in mouse skeletal muscle were negatively correlated with circulating insulin in vivo. Together, our findings shed new light on the mechanisms underlying hyperinsulinemia-induced insulin resistance in muscle cells, which are likely to be relevant in the pathogenesis of type 2 diabetes.
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