Investigating New Therapeutic Strategies Targeting Hyperinsulinemia's Mitogenic Effects in a Female Mouse Breast Cancer Model

Abstract

Epidemiological and experimental studies have identified hyperinsulinemia as an important risk factor for breast cancer induction and for the poor prognosis in breast cancer patients with obesity and type 2 diabetes. Recently it was demonstrated that both the insulin receptor (IR) and the IGF-IR mediate hyperinsulinemia's mitogenic effect in several breast cancer models. Although IGF-IR has been intensively investigated, and anti-IGF-IR therapies are now in advanced clinical trials, the role of the IR in mediating hyperinsulinemia's mitogenic effect remains to be clarified. Here we aimed to explore the potential of IR inhibition compared to dual IR/IGF-IR blockade on breast tumor growth. To initiate breast tumors, we inoculated the mammary carcinoma Mvt-1 cell line into the inguinal mammary fat pad of the hyperinsulinemic MKR female mice, and to study the role of IR, we treated the mice bearing tumors with the recently reported high-affinity IR antagonist-S961, in addition to the well-documented IGF-IR inhibitor picropodophyllin (PPP). Although reducing IR activation, with resultant severe hyperglycemia and hyperinsulinemia, S961-treated mice had significantly larger tumors compared to the vehicle-treated group. This effect maybe secondary to the severe hyperinsulinemia mediated via the IGF-1 receptor. In contrast, PPP by partially inhibiting both IR and IGF-IR activity reduced tumor growth rate with only mild metabolic consequences. We conclude that targeting (even partially) both IR and IGF-IRs impairs hyperinsulinemia's effects in breast tumor development while simultaneously sparing the metabolic abnormalities observed when targeting IR alone with virtual complete inhibition.

Highly specific role of the insulin receptor in breast cancer progression

“…Western blot and densitometric analyses were carried out for protein detection in cells and tumor tissues as described previously (Rostoker et al 2013). The following antibodies were used: phospho-IRβ Y1150/51 /IGFIRβ Y1135/36 , IRβ, IGF1R, phospho-Akt (Thr308) , total Akt, phospho-p44/42 (Thr202/Tyr204) MAPK, total p44/42-MAPK (Erk1/2), and β-actin purchased from Cell Signaling Technology (Danvers, MA, USA), followed by a matched secondary antibody conjugated with HRP (Jackson Laboratories, Bar Harbor, ME, USA).…”

“…We have recently demonstrated that dual inhibition of both IR and IGF1R could reduce mammary tumor growth rate (Rostoker et al 2013). In the current study, we employed short hairpin RNA (shRNA) technology to distinguish between the roles of the IR and IGF1R in mammary tumor growth.…”

Cancer-drug induced insulin resistance: Innocent bystander or unusual suspect

“…In rodent studies different IR/IGF1R inhibitors had drastically different effects on glucose homeostasis. Mice treated with the peptide IR antagonist S961 developed severe hyperglycaemia [55]. In contrast, mice treated with the TKI BMS-536924, a dual IR/IGF1R inhibitor, for 4 weeks displayed reduced tumour growth and showed no sign of metabolic toxicity [56].…”

A model of spontaneous mouse mammary tumor for human estrogen receptor- and progesterone receptor-negative breast cancer

“…Mouse models are excellent tools to understand the natural biology of breast cancer. Since human breast cancers are clustered into several phenotypes (subtypes) based on grade and molecular markers, a good animal model for a subtype is one which mimics most subtype characteristics morphology, molecular markers, metastatic pattern, grade, hormone-dependency, parity/pregnancy status and so on (3–5). …”