Repression of cancer protective genes by 17beta-estradiol: ligand-dependent interaction between human Nrf2 and estrogen receptor alpha.

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 17beta-estradiol (E(2)) 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. E(2)-bound ERalpha, but not ERbeta, 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 ERalpha result in a constitutive repression of Nrf2-mediated transcription. Finally, E(2)-bound ERalpha co-immunoprecipitates with Nrf2. Repression of Nrf2-mediated transcription by E(2)-bound ERalpha expands our knowledge of E(2)-regulated genes and provides a potential drug-screening target for the development of selective estrogen receptor modulators with a lower risk of causing cancer.

In vitro and in vivo regulation of antioxidant response element-dependent gene expression by estrogens.

Understanding estrogen's regulation of phase II detoxification enzymes is important in explaining how estrogen exposure increases the risk of developing certain cancers. Phase II enzymes such as glutathione-S-transferases (GST) and quinone reductase protect against developing chemically induced cancers by metabolizing reactive oxygen species. Phase II enzyme expression is regulated by a cis-acting DNA sequence, the antioxidant response element (ARE). It has previously been reported that several antiestrogens, but not 17beta-estradiol, could regulate ARE-mediated gene transcription. Our goal was to determine whether additional estrogenic compounds could regulate ARE-mediated gene expression both in vitro and in vivo. We discovered that physiological concentrations (10 nm) of 17beta-estradiol repressed GST Ya ARE-dependent gene expression in vitro. Treatment with other endogenous and anti-, xeno-, and phytoestrogens showed that estrogen receptor/ARE signaling is ligand, receptor subtype, and cell type specific. Additionally, GST and quinone reductase activities were significantly lowered in a dose-dependent manner after 17beta-estradiol exposure in the uteri of mice. In conclusion, we have shown that 17beta-estradiol, and other estrogens, down-regulate phase II enzyme activities. We propose estrogen-mediated repression of phase II enzyme activities may increase cellular oxidative DNA damage that ultimately can result in the formation of cancer in some estrogen-responsive tissues.