Mammary gland tumor promotion by chronic administration of IGF1 and the insulin analogue AspB10 in the p53R270H/+WAPCre mouse model

Abstract

IntroductionInsulin analogues are structurally modified molecules with altered pharmaco-kinetic and -dynamic properties compared to regular human insulin used by diabetic patients. While these compounds are tested for undesired mitogenic effects, an epidemiological discussion is ongoing regarding an association between insulin analogue therapy and increased cancer incidence, including breast cancer. Standard in vivo rodent carcinogenesis assays do not pick up this possible increased carcinogenic potential.MethodsHere we studied the role of insulin analogues in breast cancer development. For this we used the human relevant mammary gland specific p53R270H/+WAPCre mouse model. Animals received life long repeated treatment with four different insulin (−like) molecules: normal insulin, insulin glargine, insulin X10 (AspB10) or insulin-like growth factor 1 (IGF1).ResultsInsulin-like molecules with strong mitogenic signaling, insulin X10 and IGF1, significantly decreased the time for tumor development. Yet, insulin glargine and normal insulin, did not significantly decrease the latency time for (mammary gland) tumor development. The majority of tumors had an epithelial to mesenchymal transition phenotype (EMT), irrespective of treatment condition. Enhanced extracellular signaling related kinase (Erk) or serine/threonine kinase (Akt) mitogenic signaling was in particular present in tumors from the insulin X10 and IGF1 treatment groups.ConclusionsThese data indicate that insulin-like molecules with enhanced mitogenic signaling increase the risk of breast cancer development. Moreover, the use of a tissue specific cancer model, like the p53R270H/+WAPCre mouse model, is relevant to assess the intrinsic pro-carcinogenic potential of mitogenic and non-mitogenic biologicals such as insulin analogues.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0518-y) contains supplementary material, which is available to authorized users.

Non-metabolisable insulin glargine does not promote breast cancer growth in a mouse model of type 2 diabetes

“…Our findings are consistent with a previous mouse study that examined the latency time for mammary tumour development in a p53 mutant mouse model. In that study, AspB10 insulin and IGF-1 significantly decreased tumour latency compared with vehicle, but tumor latency was comparable between NPH insulin, glargine and vehicle [24]. Insulin glargine has been shown in vitro to have growth-promoting effects on specific cancer cell lines that express high levels of the IGF-1R [6, 9].…”

“…Insulin glargine has been shown in vitro to have growth-promoting effects on specific cancer cell lines that express high levels of the IGF-1R [6, 9]. The lack of mitogenicity of insulin glargine in vivo, however, was believed to be due to the rapid metabolism of glargine to its M1 metabolite [7, 9, 24]. Even after administration of high doses of insulin glargine, we found that glargine was metabolised into the M1 metabolite and did not lead to tumour progression.…”

Insulin, insulin receptors, and cancer

“…For instance B10Asp, a single amino-acid-substituted insulin analog, has increased affinity for both IR and IGF-1R and a longer residence on the receptor. These characteristics are associated with increased occurrence of mammary tumors in female rats [77][78][79].…”

The association of diabetes mellitus and insulin treatment with expression of insulin-related proteins in breast tumors

“…In vitro studies have shown that the PI3K signaling pathway [36][37][38][39] and the MAPK pathway [36,37] are significantly upregulated after stimulation of insulin analogues compared to human insulin. In mammary gland tumors of mice, expression of IR, IGF1R and p-AKT was significantly higher in insulin or insulin analogues-treated compared to vehicle-treated mice, while expression of p-ERK was only increased among tumors of mice treated with insulin analogues [21]. Our results suggest that treatment with insulin and insulin analogues increases signaling via mTOR.…”

“…In vitro, insulin analogue stimulation increases proliferation of breast cancer cells due to enhanced IGF1R (and INSR) signaling, while exposure to human insulin showed low mitogenic potential [20]. Chronic treatment with insulin-like compounds (IGF1, insulin AspB10) with strong binding affinity towards the IGF1R, decreased the tumor latency time and showed increased MAPK-ERK signaling in a mammary gland mouse model, while insulin glargine and human insulin treatment did not significantly decrease the time for tumor development compared to the vehicle-treated mice [21].…”