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  • Opinion
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NRF2 and cancer: the good, the bad and the importance of context

Abstract

Many studies of chemopreventive drugs have suggested that their beneficial effects on suppression of carcinogenesis and many other chronic diseases are mediated through activation of the transcription factor NFE2-related factor 2 (NRF2). More recently, genetic analyses of human tumours have indicated that NRF2 may conversely be oncogenic and cause resistance to chemotherapy. It is therefore controversial whether the activation, or alternatively the inhibition, of NRF2 is a useful strategy for the prevention or treatment of cancer. This Opinion article aims to rationalize these conflicting perspectives by critiquing the context dependence of NRF2 functions and the experimental methods behind these conflicting data.

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Figure 1: Suppression of NRF2 activity by KEAP1, and disruption by drugs or mutations.
Figure 2: A model for the importance of the context of tumour stage for the biological consequences of NRF2 activation.
Figure 3: Beneficial or carcinogenic effects of fumarate depend on its dose and the presence or absence of the enzyme fumarate hydratase.

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Acknowledgements

We thank G. Tuson for searching an exhaustive literature and for expert assistance in the preparation of the manuscript and figures, and T. Kensler for helpful comments.

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Correspondence to Michael B. Sporn or Karen T. Liby.

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Michael B. Sporn and Karen T. Liby have received grant support from Reata Pharmaceuticals. They are inventors on several patents pertaining to triterpenoids. They have received a one-time honourarium from Abbott Laboratories for a lecture on triterpenoid research. They have no equity of any sort with respect to any company in the pharmaceutical industry.

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Sporn, M., Liby, K. NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer 12, 564–571 (2012). https://doi.org/10.1038/nrc3278

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