Mark Day Lab: Frohlich

Researching Nrf2...

The role of reactive oxygen species (ROS) in cancer has been studied extensively for a number of years and it is accepted that oxidative damage to DNA resulting from elevated ROS levels play a part in the onset of cancer. It is also believed that even with the extensive armament of cellular antioxidants and detoxification enzymes, alterations in these defense mechanisms occur that lead to mutations and promote tumorigenesis. My research focuses on the transcription factor Nuclear factor E2-related factor 2 (Nrf2), which has been demonstrated to regulate the expression of antioxidant proteins and enzymes, such as glutathione-s-transferase mu isoforms, which detoxify secondary metabolites of oxidative stress. Interestingly, multiple human prostate cancer microarrays have shown that Nrf2 is down regulated in primary prostate tumors. However, it is unknown if the loss of Nrf2 results in DNA damage in the prostate. We have recently determined that Nrf2 is down regulated at both the mRNA and protein level in Rb-/-PrE cells and with tumor progression in TRAMP mouse prostate. We have found evidence that there are increased endogenous ROS levels in Rb-/-PrE cells compared to PrE cells. In addition, GST detoxification activity is decreased in Rb-/-PrE and with tumor progression in TRAMP mouse prostate. We have also found evidence that there is increased DNA damage in Rb-/-PrE cells compared to PrE cells both endogenously and in response to stress. These findings provide the rational for future studies, in which we will determine the role of Nrf2 in ROS generation, DNA damage and malignant transformation.