Repression of cancer protective genes by 17β-estradiol: Ligand-dependent interaction between human Nrf2 and estrogen receptor α

Repression of cancer-protective phase II enzymes may help explain why estrogen exposure leads to the development of cancer. In an earlier report we described the ability of 17β-estradiol (E₂) to repress phase II enzyme activity in vivo. Phase II enzymes are coordinately regulated via the presence of the antioxidant response element (ARE) in their promoter. We wanted to determine if estrogen receptors (ER) repress ARE-dependent gene expression through a mechanism that requires interaction with Nrf2, the transcription factor that regulates ARE-mediated gene transcription. E₂-bound ERα, but not ERβ, represses ARE-regulated gene expression in the presence of exogenously expressed Nrf2 as well as when the transactivation domain of Nrf2 was fused to a heterologous DNA-binding domain. Deletion of the activation function-2 (AF-2) and the ligand-binding domain of ERα result in a constitutive repression of Nrf2-mediated transcription. Finally, E ₂-bound ERα co-immunoprecipitates with Nrf2. Repression of Nrf2-mediated transcription by E₂-bound ERα expands our knowledge of E₂-regulated genes and provides a potential drug-screening target for the development of selective estrogen receptor modulators with a lower risk of causing cancer.