Pharmacologic inhibition of insulin receptor tyrosine kinase activity has antineoplastic effects similar to alloxan-induced insulin deficiency with less acute metabolic toxicity

Recent population studies provide evidence that individuals with high circulating insulin levels have a poor prognosis and/or increased risk of cancer development; however, laboratory studies concerning the role of insulin in breast cancer biology are sparse. We compared the growth of 4T1 murine breast cancer allografts in control mice, alloxan-induced hypoinsulinemic mice, and mice treated with the insulin/insulin-like growth factor-1 receptor tyrosine kinase inhibitor BMS-536924. Both interventions significantly decreased tumor growth versus control and decreased pathway activation downstream of the insulin receptor as reflected by Aktser473 phosphorylation status in the neoplastic tissue. Alloxan-treated mice exhibited signs of insulin deficiency, while BMS-536924-treated animals showed only minor metabolic derangements. Skeletal muscle displayed reduced pAktser473 in alloxan-treated mice. In contrast, BMS-536924 treatment increased pAktser473 in muscle. This raises the possibility that the relative lack of metabolic toxicity of BMS-536924 involves varying tissue levels of the drug. These results support the view that host insulin physiology is a potentially modifiable determinant of breast cancer behaviour