Urpilainen Elina, Kangaskokko Jenni, Puistola Ulla, Karihtala Peeter
1 Department of Obstetrics and Gynaecology, PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.
2 Department of Pathology and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.
Tumour Biol. 2019 Jan;41(1):1010428318815413. doi: 10.1177/1010428318815413.
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.
核因子（红细胞衍生 2）样 2（Nrf2）是氧化应激反应的主要调节因子，它受到 Kelch 样 ECH 相关蛋白 1（Keap1）的负调控。Keap1-Nrf2 轴在致癌过程中起着重要作用。在先前的研究中，广泛使用的糖尿病药物二甲双胍似乎在 Nrf2 功能调节中起关键作用。在本研究中，我们对 157 例接受根治性乳腺癌手术的 2 型糖尿病患者进行了 Nrf2 和 Keap1 的免疫组织化学表达评估。这些患者中，共有 78 例（49.7%）在乳腺癌诊断时单独服用二甲双胍或与其他口服抗糖尿病药物联合使用。我们发现，高水平的细胞质 Nrf2 表达预示着总体生存率和乳腺癌特异性生存率较差，但仅在诊断时未服用二甲双胍的患者中如此。同样，低水平的细胞核 Keap1 表达在未服用二甲双胍的患者的总体生存率和乳腺癌特异性生存率方面具有不良预后价值。另一方面，高水平的细胞核 Keap1 表达与总体生存率和乳腺癌特异性生存率的延长相关。尽管需要更多的机制性临床前和前瞻性临床研究，但这些结果可能可以用 Keap1 功能失调或移位来解释。
