Metformin diminishes the unfavourable impact of Nrf2 in breast cancer patients with type 2 diabetes

Abstract

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a major regulator of the oxidative stress response and it is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1). The Keap1–Nrf2 axis has a fundamental role in carcinogenesis. In previous studies, the widely used diabetes drug metformin has appeared to have a critical role in the regulation of Nrf2 function. In this study, we assessed the expression of Nrf2 and Keap1 immunohistochemically in 157 patients with type 2 diabetes who underwent breast cancer surgery with curative intent. In total, 78 (49.7%) of these patients were taking metformin alone or combined with other oral anti-diabetic medication at the time of breast cancer diagnosis. We found that high-level cytoplasmic Nrf2 expression predicted dismal overall survival and breast cancer–specific survival, but only in the patients who were not taking metformin at the time of diagnosis. Similarly, low-level nuclear Keap1 expression had an adverse prognostic value in terms of overall survival and breast cancer–specific survival in patients without metformin. On the other hand, high-level nuclear Keap1 expression was associated with prolonged overall survival and breast cancer–specific survival. The results may be explained in terms of non-functioning or displaced Keap1, although more mechanistic pre-clinical and prospective clinical studies are warranted.