Alternative signaling network activation through different insulin receptor family members caused by pro-mitogenic antidiabetic insulin analogues in human mammary epithelial cells

INTRODUCTION: Insulin analogues are designed to have improved pharmacokinetic parameters compared to regular human insulin. This provides a sustained control of blood glucose levels in diabetic patients. All novel insulin analogues are tested for their mitogenic side effects, however these assays do not take into account the molecular mode of action of different insulin analogues. Insulin analogues can bind the insulin receptor and the insulin-like growth factor 1 receptor with different affinities and consequently will activate different downstream signaling pathways. METHODS: Here we used a panel of MCF7 human breast cancer cell lines that selectively express either one of the isoforms of the INSR or the IGF1R. We applied a transcriptomics approach to assess the differential transcriptional programs activated in these cells by either insulin, IGF1 or X10 treatment. RESULTS: Based on the differentially expressed genes between insulin versus IGF1 and X10 treatment, we retrieved a mitogenic classifier gene set. Validation by RT-qPCR confirmed the robustness of this gene set. The translational potential of these mitogenic classifier genes was examined in primary human mammary cells and in mammary gland tissue of mice in an in vivo model. The predictive power of the classifier genes was evaluated by testing all commercial insulin analogues in the in vitro model and defined X10 and glargine as the most potent mitogenic insulin analogues. CONCLUSIONS: We propose that these mitogenic classifier genes can be used to test the mitogenic potential of novel insulin analogues as well as other alternative molecules with an anticipated affinity for the IGF1R. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13058-015-0600-5) contains supplementary material, which is available to authorized users

GENETIC SUSCEPTIBILITY TO RESPIRATORY SYNCYTIAL VIRUS BRONCHIOLITIS IN PRETERM CHILDREN IS ASSOCIATED WITH AIRWAY REMODELING GENES AND INNATE IMMUNE GENES

Prematurity is a risk factor for severe respiratory syncytial virus bronchiolitis. We show that genetic factors in innate immune genes (IFNA13, IFNAR2, STAT2. IL27, NFKBIA, C3, IL1RN, TLR5), in innate and adaptive immunity (IFNG), and in airway remodeling genes (ADAM33 and TGFBR1), affect disease susceptibility to a different extent in preterm children, born with underdeveloped lungs, than in term children

Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes

Background. Respiratory syncytial virus (RSV) is a common cause of severe lower respiratory tract infection in infants. Only a proportion of children infected with RSV require hospitalization. Because known risk factors for severe disease, such as premature birth, cannot fully explain differences in disease severity, genetic factors have been implicated. Methods. To study the complexity of RSV susceptibility and to identify the genes and biological pathways involved in its development, we performed a genetic association study involving 470 children hospitalized for RSV bronchiolitis, their parents, and 1008 random, population controls. We analyzed 384 single - nucleotide polymorphisms (SNPs) in 220 candidate genes involved in airway mucosal responses, innate immunity chemotaxis, adaptive immunity, and allergic asthma. Results. SNPs in the innate immune genes VDR (rs10735810; P = .0017), JUN (rs11688; P = .0093), IFNA5 (rs10757212; P = .0093), and NOS2 (rs1060826; P = .0031) demonstrated the strongest association with bronchiolitis. Apart from association at the allele level, these 4 SNPs also demonstrated association at the genotype level (P = .0056, P = .0285, P = .0372, and P = .0117 for the SNPs in VDR, JUN, IFNA5, and NOS2, respectively). The role of innate immunity as a process was reinforced by association of the whole group of innate immune SNPs when the global test for groups of genes was applied (P = .046) Conclusion. SNPs in innate immune genes are important in determining susceptibility to RSV bronchiolitis

Toll-like receptor 4 polymorphism associated with the response to whole-cell pertussis vaccination in children from the KOALA study

We examined the association between haplotype tagging single-nucleotide polymorphisms in TLR4 and the pertussis toxin-specific immunoglobulin G response after whole-cell pertussis (wP) vaccination in 515 1-year-old children from the KOALA study. A lower titer was associated with the minor allele of rs2770150, supporting a role for Toll-like receptor 4 in the antibody response to wP vaccination

Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD: A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies. RESULTS: In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations. CONCLUSION: There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways

Treatment with insulin (analogues) and breast cancer risk in diabetics:a systematic review and meta-analysis of in vitro, animal and human evidence

INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD: A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies. RESULTS: In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations. CONCLUSION: There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways

Comparing rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals : on systemic dose and developmental effects

A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects between rat and rabbit study outcomes for individual compounds, EFDT studies in two species have added value over single studies

Comparing rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on systemic dose and developmental effects

A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects between rat and rabbit study outcomes for individual compounds, EFDT studies in two species have added value over single studies