The role of Nrf2 in increased reactive oxygen species and DNA damage in prostate tumorigenesis.

The impact of oxidative stress in human cancer has been extensively studied. It is accepted that elevated reactive oxygen species (ROS) promote mutagenic DNA damage. Even with an extensive armament of cellular antioxidants and detoxification enzymes, alterations to DNA occur that initiate cellular transformation. Erythroid 2p45 (NF-E2)-related factor 2 (Nrf2) is a basic-region leucine zipper transcription factor that mediates the expression of key protective enzymes through the antioxidant-response element (ARE). By analysing 10 human prostate cancer microarray data sets, we have determined that Nrf2 and members of the glutathione-S-transferase (GST) mu family are extensively decreased in human prostate cancer. Using the TRAMP transgene and Rb and Nrf2 knockout murine models, we demonstrated that the loss of Nrf2 initiates a detrimental cascade of reduced GST expression, elevated ROS levels and ultimately DNA damage associated with tumorigenesis. Based on overwhelming data from clinical samples and the current functional analysis, we propose that the disruption of the Nrf2-antioxidant axis leads to increased oxidative stress and DNA damage in the initiation of cellular transformation in the prostate gland.