Type 2 diabetes is characterized by insulin resistance — poor glucose utilization by peripheral tissues such as skeletal muscle — and compensatory increase in circulating insulin levels (hyperinsulinemia) and hyperglycemia. Hyperinsulinemia increases insulin-like growth factor (IGF) which is correlated with an increased risk of breast cancer. Hyperinsulinemia also decreases the plasma levels of insulin-like growth factor-binding protein 1 (IGF-BP1), and thus increases the levels of bioactive IGF-1.3

Three biological pathways have been proposed to explain the pathophysiological basis of increased breast cancer risk in diabetic patients: activation of the insulin pathway, activation of the IGF signaling transduction pathways, and dysregulated sex-hormone signaling pathways.4 Insulin and IGF-1 (or IGF-2) bind to their respective receptors and activate common signaling mediators, such as RAS-RAF-MEK-ERK MAP kinase pathway, and PI3K-AKT kinase pathway.  MAP kinase and AKT kinase pathways are key signal-transduction pathways promoting cell proliferation and preventing apoptosis. (Figure 1) Breast cancer cells express high levels of insulin receptor (IR), insulin-like growth factor receptor (IGFR), and IGFR/IR hybrid receptor. Breast cancer patients with diabetes also have high plasma levels of estrogens and androgens, low sex-hormone binding globulin levels,4 and high levels of inflammatory mediators which promote tumor growth and metastasis.9 Patients with preexisting diabetes may also preclude aggressive or even optimal cancer treatment due to increased incidence of treatment-related complications.5 In addition, these patients have higher risk of hospitalizations, due to chemotherapy-associated toxicities, such as neutropenia, anemia, or any cause (OR, 1.38; 95% CI=1.23, 1.56).6

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Figure 1: Insulin, IGF pathways and cancer.10