Issues

Lynch syndrome (LS) is the most common familial cancer syndrome, caused by a mutation in one of the mismatch repair genes, such as MSH2. Due to the early onset of tumor development and a high lifetime risk of developing colorectal cancer, identifying novel chemopreventive targets is essential. One such target could be NRF2, a protein that reduces cellular oxidative stress but can also be overexpressed in tumors to promote their development. In the study starting on page 311, Haller and colleagues found that NRF2 expression and downstream signaling were overexpressed in mouse and human MSH2-associated LS. Deletion of NRF2 increased oxidative stress but reduced tumorigenesis. The cover image is adapted from Figure 3, which shows increased oxidative DNA damage in mice with an NRF2 knockout. NRF2 deficiency was also associated with lower intestinal cell proliferation, as measured by Ki67 immunohistochemistry, due to reduced cytoplasmic and nuclear β-Catenin expression. These results suggest that NRF2 drives tumorigenesis in MSH2-associated LS, and targeting NRF2 could be a promising approach.