Nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a transcription factor that orchestrates diverse stress signaling and protects cells from oxidative or electrophilic stress by leading various transcriptional programmes. The studies about this regulatory protein and its negative regulator, Kelch-like ECH-associated protien 1 (Keap1) have been conducted internationally and have awoken many people's concern in a key controversy. The controversy is centred around whether Nrf2 acts as a tumor suppressive function or an oncogenic function, leading to the question of whether Nrf2 could be targeted for chemopreventive and anticancer therapeutic method. In abundant publications of chemopreventive drugs, enhancement of the Nrf2 activity may have beneficial effects on suppression of carcionogenesis and prevention a range of other chronic diseases. However, recent many reports have found that enhanced Nrf2 activity possesses oncogenic capacity. Indeed, gain-of-function mutations in Nrf2 and loss-of-function mutation in Keap1 are found in most cancers, although the frequencies of mutations are often low. More importantly, it has been shown that constantly high levels of Nrf2 expression and low level of Keap1 may be related with chemotherapy resistance and poor prognosis. It is therefore debatable whether the activation, or alternatively the inhibition, of Nrf2 is a practical approach to the prevention or treatment of cancer. This review primarily focuses on the various domain structures of Nrf2 and Keap1, the interaction among Nrf2 and Keap1, and then attempts to find the resolution of the paradox. (Cancer Prev Res 17, 0-195, 2012)

Keywords: Nrf2, Keap1, Cancer, Oxidative stress