Insulin Receptor Phosphorylation by Endogenous Insulin or the Insulin Analog AspB10 Promotes Mammary Tumor Growth Independent of the IGF-I Receptor

Abstract

Endogenous hyperinsulinemia and insulin receptor (IR)/IGF-I receptor (IGF-IR) phosphorylation in tumors are associated with a worse prognosis in women with breast cancer. In vitro, insulin stimulation of the IR increases proliferation of breast cancer cells. However, in vivo studies demonstrating that IR activation increases tumor growth, independently of IGF-IR activation, are lacking. We hypothesized that endogenous hyperinsulinemia increases mammary tumor growth by directly activating the IR rather than the IGF-IR or hybrid receptors. We aimed to determine whether stimulating the IR with the insulin analog AspB10 could increase tumor growth independently of IGF-IR signaling. We induced orthotopic mammary tumors in control FVB/n and hyperinsulinemic MKR mice, and treated them with the insulin analog AspB10, recombinant human IGF-I, or vehicle. Tumors from mice with endogenous hyperinsulinemia were larger and had greater IR phosphorylation, but not IGF-IR phosphorylation, than those from control mice. Chronic AspB10 administration also increased tumor growth and IR (but not IGF-IR) phosphorylation in tumors. IGF-I led to activation of both the IGF-IR and IR and probably hybrid receptors. Our results demonstrate that IR phosphorylation increases tumor growth, independently of IGF-IR/hybrid receptor phosphorylation, and warrant consideration when developing therapeutics targeting the IGF-IR, but not the IR.

Antihyperglycaemic therapies and cancer risk

“…Therefore, hyperinsulinaemia may exert mitogenic effects mediated through the IGF1R, but as it was recently demonstrated in mice in vivo using the mitogenic insulin analogue AspB10, the mitogenic effects can also be exerted through the IR itself. 190 In parallel, it was also shown in previous in vitro studies that the IR, predominantly the more mitogenic IR-A isoform, is overexpressed in many types of cancer, [191][192][193][194][195] and insulin as well as insulin analogues appears to be able to stimulate the growth of various tumour cells in vitro through IR-A, although the existing data revealed some heterogeneity. [196][197][198][199] Here, we will focus on insulin analogues in humans trying to clarify the safety concerns raised by the in vitro studies.…”

Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality

“…Similarly, when cells overexpressing the Neu (ortholog of human epidermal growth factor receptor 2, HER2) or c-myc/vegf oncogenes were injected orthotopically into mammary glands, the tumors grew more rapidly in the hyperinsulinemic female MKR mice (51,147). Reducing insulin levels in the MKR mice using a ␤-3 adrenergic receptor agonist (CL-316,243) or blocking the IR and IGF-IR using a tyrosine kinase inhibitor reduced the growth of the primary tumors in the female MKR mice; conversely, administration of a mitogenic insulin analog increased tumor growth and metastases in the MKR mice (51,55,59,147). These results support the hypothesis that endogenous hyperinsulinemia enhances primary breast cancer growth by activation of the IR and/or IGF-IR.…”

Pretreatment Insulin Levels as a Prognostic Factor for Breast Cancer Progression

“…Hyperinsulinemia, insulin resistance (IR) [7,8,10], and enhanced levels of insulin-like growth factor-1 (IGF-1) [11] have all been proposed as the underlying causative mechanisms, mainly on the basis of in vitro and animal studies supporting a role for insulin, insulin receptor, and IGFs in BC initiation [12][13][14] and progression [15]. These experimental findings are strengthened by indirect observations that metformin, a biguanide oral hypoglycemic agent capable of lowering insulin levels and improving IR, also might The Oncologist 2016;21:1041-1049 www.TheOncologist.com ©AlphaMed Press 2016 be effective in reducing BC incidence [8] and may beneficially act on proliferation and apoptosis markers in early BC stages [16][17][18].…”