Insulin-like growth factor 1 receptor activation promotes mammary gland tumor development by increasing glycolysis and promoting biomass production.
Background: The insulin-like growth factor 1 (IGF1) signaling axis plays a major role in tumorigenesis. In a previous experiment, we chronically treated mice with several agonists of the IGF1 receptor (IGF1R). We found that chronic treatment with insulin analogues with high affinity towards the IGF1...
| Publicado en: | Breast Cancer Research Vol. 19; pp. 1 - 16 |
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| Autores principales: | , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
BioMed Central
2/7/2017
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=121200513&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 121200513 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14655411 8UYJ jtl: Breast Cancer Research issn: 14655411 maglogo: N pubinfo: dt: 2/7/2017 vid: 19 pid: 24147 pub: BioMed Central artinfo: ui: 121200513 121200513 NLM28173837 121200513 10.1186/s13058-017-0802-0 NLM28173837 121200513 ppf: 1 ppct: 15 formats: fmt: @attributes: type: P tig: atl: Insulin-like growth factor 1 receptor activation promotes mammary gland tumor development by increasing glycolysis and promoting biomass production. aug: au: Braak, Bas ter Siezen, Christine L. Lee, Joo S. Rao, Pooja Voorhoeve, Charlotte Ruppin, Eytan van der Laan, Jan Willem van de Water, Bob Ter Braak, Bas affil: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands sug: subj: Breast Neoplasms Pathology Breast Neoplasms Metabolism Glucose Metabolism Mice Cell Movement Breast Neoplasms Female Signal Transduction Gene Expression Profiling Body Weights and Measures Prognosis Cell Line, Tumor Somatomedins Metabolism Somatomedins Pharmacodynamics Insulin Metabolism Proteins Animals Mutation Glycolysis Breast Neoplasms Mortality Female ab: Background: The insulin-like growth factor 1 (IGF1) signaling axis plays a major role in tumorigenesis. In a previous experiment, we chronically treated mice with several agonists of the IGF1 receptor (IGF1R). We found that chronic treatment with insulin analogues with high affinity towards the IGF1R (IGF1 and X10) decreased the mammary gland tumor latency time in a p53R270H/+WAPCre mouse model. Frequent injections with insulin analogues that only mildly activated the IGF1R in vivo (glargine and insulin) did not significantly decrease the tumor latency time in this mouse model.Methods: Here, we performed next-generation RNA sequencing (40 million, 100 bp reads) on 50 mammary gland tumors to unravel the underlying mechanisms of IGF1R-promoted tumorigenesis. Mutational profiling of the individual tumors was performed to screen for treatment-specific mutations. The transcriptomic data were used to construct a support vector machine (SVM) classifier so that the phenotypic characteristics of tumors exposed to the different insulin analogue treatments could be predicted. For translational purposes, we ran the same classifiers on transcriptomic (micro-array) data of insulin analogue-exposed human breast cancer cell lines. Genome-scale metabolic modeling was performed with iMAT.Results: We found that chronic X10 and IGF1 treatment resulted in tumors with an increased and sustained proliferative and invasive transcriptomic profile. Furthermore, a Warburg-like effect with increased glycolysis was observed in tumors of the X10/IGF1 groups and, to a lesser extent, also in glargine-induced tumors. A metabolic flux analysis revealed that this enhanced glycolysis programming in X10/IGF1 tumors was associated with increased biomass production programs. Although none of the treatments induced genetic instability or enhanced mutagenesis, mutations in Ezh2 and Hras were enriched in X10/IGF1 treatment tumors.Conclusions: Overall, these data suggest that the decreased mammary gland tumor latency time caused by chronic IGF1R activation is related to modulation of tumor progression rather than increased tumor initiation. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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