Selective Activation of Estrogen Receptor-β Target Genes by 3,3′-Diindolylmethane

3,3′-Diindolylmethane (DIM) is a natural compound found in cruciferous vegetables that has antiproliferative and estrogenic activity. However, it is not clear whether the estrogenic effects are mediated through estrogen receptor (ER)α, ERβ, or both ER subtypes. We investigated whether DIM has ER subtype selectivity on gene transcription. DIM stimulated ERβ but not ERα activation of an estrogen response element upstream of the luciferase reporter gene. DIM also selectively activated multiple endogenous genes through ERβ. DIM did not bind to ERβ, indicating that it activates genes by a ligand-independent mechanism. DIM causes ERβ to bind regulatory elements and recruit the steroid receptor coactivator (SRC)-2 coactivator, which leads to the activation of ER target genes. Silencing of SRC-2 inhibited the activation of ER target genes, demonstrating that SRC-2 is required for transcriptional activation by DIM. Our results demonstrate that DIM is a new class of ERβ-selective compounds, because it does not bind to ERβ, but instead it selectively recruits ERβ and coactivators to target genes.