Insulin-like growth factor 1 receptor activation promotes mammary gland tumor development by increasing glycolysis and promoting biomass production.
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.



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.



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.



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.
Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands.
Bas
B
Ter Braak
Medicines Evaluation Board (MEB), Graadt van Roggenweg 500, 3531, AH, Utrecht, The Netherlands.
Christine L
CL
Siezen
The Blavatnik School of Computer Science, Tel-Aviv University, Tel Aviv, 69978, Israel.
Joo S
JS
Lee
ServiceXS, Plesmanlaan 1 /D, 2333, BZ, Leiden, The Netherlands.
Pooja
P
Rao
Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands.
Charlotte
C
Voorhoeve
The Blavatnik School of Computer Science, Tel-Aviv University, Tel Aviv, 69978, Israel.
Eytan
E
Ruppin
Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands. jw.vd.laan@cbg-meb.nl.|Medicines Evaluation Board (MEB), Graadt van Roggenweg 500, 3531, AH, Utrecht, The Netherlands. jw.vd.laan@cbg-meb.nl.|Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Antonie van Leeuwenhoeklaan 9, 3721, MA, Bilthoven, The Netherlands. jw.vd.laan@cbg-meb.nl.
Jan Willem
JW
van der Laan
Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands. b.water@lacdr.leidenuniv.nl.
Bob
B
van de Water
D000818:Animals; D015415:Biomarkers; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011379:Prognosis; D017526:Receptor, IGF Type 1 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome; D047368:Tumor Burden; D018631:ras Proteins / Q000235:genetics
D015415:Biomarkers; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D017526:Receptor, IGF Type 1; D018631:ras Proteins; D005947:Glucose
Hallmarks of cancer; IGF1R; Mammary gland tumor; Next-generation sequencing; Warburg