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

P J Ansell1, S-C Lo, L G Newton

  • 1Department of Biochemistry, University of Missouri, Columbia, MO, USA.

Molecular and Cellular Endocrinology
|October 4, 2005
PubMed

Insights

Estrogen exposure can increase cancer risk by repressing cancer-protective enzymes. Estrogen receptor alpha (ERalpha) directly interacts with Nrf2 to suppress protective gene activity, offering a new drug target.

Area of Science:

  • Molecular biology
  • Cancer research
  • Endocrinology

Background:

  • Estrogen exposure is linked to increased cancer development.
  • Estrogen may cause cancer by repressing cancer-protective phase II enzymes.
  • Phase II enzymes are regulated by the antioxidant response element (ARE).

Purpose of the Study:

  • To investigate if estrogen receptors (ER) repress ARE-dependent gene expression via interaction with Nrf2.
  • To understand the mechanism of estrogen-induced repression of cancer-protective genes.

Main Methods:

  • Studied the effect of 17beta-estradiol (E(2)) on ARE-regulated gene expression in the presence of Nrf2.
  • Utilized deletion mutants of ERalpha to identify key domains for repression.
  • Performed co-immunoprecipitation to assess the interaction between ERalpha and Nrf2.

Main Results:

  • E(2)-bound ERalpha, not ERbeta, repressed ARE-regulated gene expression.
  • ERalpha repressed Nrf2-mediated transcription even when Nrf2's transactivation domain was fused to another protein.
  • Deletion of ERalpha's activation function-2 and ligand-binding domains led to constitutive repression.
  • E(2)-bound ERalpha was found to co-immunoprecipitate with Nrf2.

Conclusions:

  • Estrogen receptor alpha directly represses Nrf2-mediated transcription of ARE-regulated genes.
  • This repression mechanism provides insight into estrogen's role in cancer development.
  • The interaction between ERalpha and Nrf2 presents a potential drug-screening target for novel cancer prevention strategies.

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