Highly specific role of the insulin receptor in breast cancer progression

Abstract

Accumulating evidence from clinical trials indicates that specific targeting of the IGF1 receptor (IGF1R) is not efficient as an anti-breast cancer treatment. One possible reason is that the mitogenic signals from the insulin receptor (IR) can be processed independently or as compensation to inhibition of the IGF1R. In this study, we highlight the role of the IR in mediating breast tumor progression in both WT mice and a hyperinsulinemic MKR mouse model by induction of Ir (Insr) or Igf1r knockdown (KD) in the mammary carcinoma Mvt-1 cell line. By using the specific IR antagonist-S961, we demonstrated that Igf1r-KD induces elevated responses by the IR to IGF1. On the other hand, Ir-KD cells generated significantly smaller tumors in the mammary fat pads of both WT and MKR mice, as opposed to control cells, where as the Igf1r-KD cells did not. The tumorigenic effects of insulin on the Mvt-1 cells were also demonstrated using microarray analysis, which indicates alteration of genes and signaling pathways involved in proliferation, the cell cycle, and apoptosis following insulin stimulation. In addition, the correlation between IR and the potential prognostic marker for aggressive breast cancer, CD24, was examined in the Ir-KD cells. Fluorescence-activated cell sorting (FACS) analysis revealed more than 60% reduction in CD24 expression in the Ir-KD cells when compared with the control cells. Our results also indicate that CD24-expressing cells can restore, at least in part, the tumorigenic capacity of Ir-KD cells. Taken together, our results highlight the mitogenic role of the IR in mammary tumor progression with a direct link to CD24 expression.

Using Phosphatidylinositol Phosphorylation as Markers for Hyperglycemic Related Breast Cancer

“…Taken together, it suggests a significant role for changing expression levels of the different PI phosphorylation species in the dysregulation of normal cell-cell contacts, cell polarization, signal transduction, and membrane trafficking events [4,6,7,33,34]. While it is understood that many factors play a role in this T2D-cancer nexus (e.g., pharmaceutical treatments [9,13,33,35], hyperinsulinemia [3,12], and inflammation [5,[36][37][38][39]), there is significant evidence that increased glucose metabolism, and therefore a hyperglycemic microenvironment, is fundamental in the development of cancer [12,40]. Hence, we endeavored to determine the T2D glycemic effects on the cancerous microenvironment by studying the related changes in the PI phosphorylation profile.…”

Insulin, insulin receptors, and cancer

“…A better understanding of the IR role in cancer may have important implications considering that clinical trials indicate that inhibitors specifically targeting the IGF-1R are not efficient for inhibiting cancer [95,96] and one possible reason is that the mitogenic signal might be independently processed by the IR, even as compensation to the inhibition of the IGF-1R. Indeed, a recent experimental study has suggested a highly specific role of the IR in breast cancer progression [97].…”

Dual Targeting of Insulin Receptor and KIT in Imatinib-Resistant Gastrointestinal Stromal Tumors

“…13,14). IR and IGF1/2R have essential roles in energy metabolism, cell growth, division, and differentiation (15)(16)(17), and various studies suggest that aberrant IR/IGF1/2R signaling drives tumorigenesis in breast, lung, hepatocellular, and pancreatic cancers (18)(19)(20)(21)(22). IGF1R has been shown to be overexpressed in wild-type and pediatric GIST (23,24) and is a potential therapeutic target in GIST lacking KIT and PDGFRA mutations (25).…”