In 2012, Rojo et al. observed that a cancer-chemopreventive agent, nordihydroguaiaretic acid (NDGA), increased the level of Nrf2 protein and expression of HO-1 in wild-type mouse embryo fibroblasts (MEFs) and in Keap1(-/-) MEFs, but not in Nrf2(-/-) MEFs, implying that Keap1-independent mechanisms regulate Nrf2 stability and HO-1 induction [52]. Here, NFE2L2 is linked to cancer.