Insulin Receptor Phosphorylation by Endogenous Insulin or the Insulin Analog AspB10 Promotes Mammary Tumor Growth Independent of the IGF-I Receptor
- Emily Jane Gallagher1,
- Nyosha Alikhani1,
- Aviva Tobin-Hess1,
- Jeffrey Blank1,
- Nicholas J. Buffin1,
- Zara Zelenko1,
- Norbert Tennagels2,
- Ulrich Werner2 and
- Derek LeRoith1⇑
- 1Division of Endocrinology, Diabetes and Bone Diseases, Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
- 2R&D Diabetes Division, Sanofi-Aventis Deutschland, Frankfurt am Main, Germany.
- Corresponding author: Derek LeRoith, .
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.
- Received February 12, 2013.
- Accepted June 21, 2013.
- © 2013 by the American Diabetes Association.
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