International Journal of Cell Biology might similarly disturb the Nrf2/Keap1 complex formation as do mutations in the same areas of Keap1 [28]. A Keap1-independent increase in the basal Nrf2 level by oncogenic alleles of Kras, Braf, and cMyc has been described recently [36]. Whereas an ectopic transduction of mouse embryonic ﬁbroblasts (MEFs) and NIH3T3 ﬁbroblasts with K-RasG12D led to an increase in the production of reactive oxygen species (ROS), inducible expression of endogenous K-RasG12D in MEFs decreased ROS production and increased Nrf2 as well as enzymes of the Nrf2 antioxidant program. The K-RasG12D mutation is commonly found in human pancreatic cancer [36]. Accordingly, higher NQO1 protein and lower levels of ROS biomarkers were detected in murine and human pancreatic intraepithelial neoplasia (PanIN) compared to normal tissue. The relevance of oncogene- mediated Nrf2 activation was proven in PanIN from Nrf2- deﬁcient mice in which K-RasG12D-induced proliferation and tumorigenesis was much less than in PanIN from wild-type (WT) mice. A relatively novel system regulated by Nrf2 is the pro- teasome, a protease complex responsible for the degradation of proteins tagged with polyubiquitin chains [37]. The 26S proteasome consists of the catalytic 20S core subunit and the 19S regulatory particle, both consisting of diﬀerent subunits. The 20S proteasome degrades oxidatively modiﬁed proteins and is activated upon mild oxidative stress [38]. The S5a subunit of the 19S proteasome and the α-5 subunit of the 20S proteasome were enhanced in colon tumors compared to the surrounding normal tissue [39]. The higher levels correlated with an elevated nuclear localization of Nrf2. Activation of Nrf2 by electrophilic stress in human colon cancer cell lines further elevated these subunits and increased TRAIL- mediated NFκB activation leading to a protection against apoptosis [39]. Also upregulation of enzymes metabolizing xenobiotics will not always improve detoxiﬁcation but increase the toxicity of xenobiotics as reviewed by Hayes et al. [40]. In fact, activated Nrf2 and upregulation of GSTP1 in hepatocarcinogenesis were the ﬁrst hint to a supportive role of Nrf2 in cancer cells [41]. Thus, enhancement of Nrf2 and the resulting upregulation of multidrug resistance-associated proteins can help cancer cells to escape from chemotherapy [42, 43]. Chemoresistance has indeed been observed after treatment of breast cancer cells with tamoxifen [44] and of ovarian cancer cells with cisplatin [45] or other drugs [46]. Accordingly, knockdown of Nrf2 prevented resistance to tamoxifen in breast cancer cells [44] and resistance to doxorubicin in MEFs from Nrf2 knock-out (KO) mice [47]. However, Nrf2 is not activated in all types of cancer cells. It is even decreased in a high number of breast cancer cells compared to normal mammary epithelial cell lines. This coincides with variable but detectable levels of Keap1 and consistently increased mRNA and protein levels of Cul3, the ubiquitin ligase tagging Nrf2 for proteasomal degradation. Accordingly, downregulation of Cul3 in MCF-7 cells rescued Nrf2 and its targets [48]. A decrease of Nrf2 in the human breast cancer cells lines MDA-MB-231 and Hs578T is caused by silencing of the Keap1 RNA-destabilizing miR200a (miRNA) leading to a higher degradation of Nrf2 [49]. 3 Taken together, cancer cells use all facets of the adaptive response to escape elimination. In consequence, under certain circumstances, the protective functions of Nrf2 can switch to procarcinogenic ones [7, 17, 28]. Nrf2 appears to be more active in some cancer cells and less in others, depending on the cell context, the nature of stress, and the cancer stage. Also Nrf2 targets may have dual roles in cancer which will here be discussed for the selenoproteins thioredoxin reductase-1 (TrxR1) [50, 51] and glutathione peroxidase-2 (GPx2) [52, 53]. 3. TrxR1 Thioredoxin reductases (TrxRs) are a family of NADPH- dependent selenoﬂavoproteins (TrxR1, TrxR2, and TGR) present in almost all living cells (for reviews see [54, 55]). Together with thioredoxin (Trx) and NADPH, they build up the thioredoxin system. The system maintains a reducing environment in the cytosol, among others required for the redox regulation of gene expression via transcription factor activity. It, thus, is involved in DNA repair, angiogenesis, and inhibition of apoptosis. Moreover, during DNA synthesis Trx directly transduces electrons to ribonucleotide reductase which requires the continuous reduction of thereby oxidized Trx by TrxR. These functions underscore the pivotal role of TrxR in cell proliferation and survival [55, 56]. Due to its antioxidant function and its upregulation in cancer cell lines [57] and human gastrointestinal cancer tissue [58], TrxR was ﬁrst expected to counteract malignant transformation. This hypothesis was supported by the fact that TrxR1 regulates the correct maturation of the tumor suppressor p53 [59, 60]. Furthermore, TrxR1 was the ﬁrst selenoprotein identiﬁed as target of Nrf2 [50, 61] which at ﬁrst glance was interpreted as support for a protective role [50, 62]. This might indeed hold true for the prevention of initiation of carcinogenesis in healthy cells. However, it soon turned out that the beneﬁcial eﬀects of the Trx/TrxR system change to its opposite during the growth and progression phase of tumors. In fact, upregulation in cancer cells might also reﬂect the need of the enzyme for essential functions in cancer cells, the TrxR-dependent synthesis of deoxyribonucleotides [63]. Downregulation of TrxR1 by antisense RNA did not increase but inhibited growth of human hepatocarcinoma cells [64]. Also a knock- down of TrxR1 in lung carcinoma cells reversed their tu- morigenicity and invasive potential in a xenograft model [65]. As underlying mechanism, the decreased expression of DNA polymerase α was supposed [66]. Alternatively, the antiapoptotic function of TrxR1 may come into play. Reduced Trx is required to inhibit apoptosis signal-regulating kinase (ASK) [67]. Lack of TrxR1 will prevent inhibition of ASK making the elimination of malignant cells by apoptosis possible. Not surprisingly, TrxRs have been suggested as potential targets for anticancer drugs [68, 69]. The inhibitory mechanism of such drugs often is the same as used for the dissociation of Nrf2 from Keap1, namely, thiol modiﬁcation. Modiﬁcation of the selenol in the active centre of TrxR1 indeed leads to an inhibition of the enzyme activity. On the