The NF-E2-related factor-2 (Nrf2) is a transcription factor which regulates the major cellular defense systems and thereby contributes to the prevention of many diseases including cancer. Selenium deficiency is associated with a higher cancer risk making also this essential trace element a promising candidate for cancer prevention. Two selenoproteins, thioredoxin reductase-1 (TrxR1) and glutathione peroxidase-2 (GPx2), are targets for Nrf2. Selenium deficiency activates Nrf2 as does a TrxR1 knockout making a synergism between both systems plausible. Although this might hold true for healthy cells, the interplay may turn into the opposite in cancer cells. The induction of the detoxifying and antioxidant enzymes by Nrf2 will make cancer cells chemoresistant and will protect them against oxidative damage. The essential role of TrxR1 in maintaining proliferation makes its upregulation in cancer cells detrimental. The anti-inflammatory potential of GPx2 will help to inhibit cancer initiation and inflammation-triggered promotion, but its growth supporting potential will also support tumor growth. This paper considers beneficial and adverse consequences of the activation of Nrf2 and the selenoproteins which appear to depend on the cancer stage. 1. Introduction An adequate-to-high selenium supply and activation of Nrf2 by dietary compounds are considered to substantially help to prevent cancer development. Selenium exerts its effects mainly as part of selenoproteins with redox functions, and Nrf2 upregulates enzymes of the adaptive response. Thus, both systems are involved in the equipment of cells with a network of enzymes which are supposed to counteract the transformation of healthy into cancer cells by oxidative damage. However, not all attempts to prevent cancer by respective dietary supplementation/intervention ended up with a beneficial outcome; even harmful effects were observed. The so-called Linxian trial was among the first large randomized, double-blind, primary prevention studies investigating a putative prevention of cancer by vitamins and trace elements. A mixture of selenium, vitamin E, and β-carotene, called factor D, significantly reduced total mortality, total cancer mortality, and most significantly mortality from gastric cancer [1]. Although selenium was not given as a single component, according to subsequent studies it appeared to have the most efficient effects [2–4]. 10 years after completion of the Linxian trial, reduction in mortality remained 5% for total and 11% for gastric cancer [5]. Considering age, the effect of factor D was
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