Agonist-dependent Repression Mediated by Mutant Estrogen Receptor α that Lacks the Activation Function 2 Core Domain

Nuclear receptor corepressor (N-CoR) and silencing mediator of retinoid and thyroid hormone receptors (SMRT) form heterogeneous complexes with various histone deacetylases (HDACs). In this report, we found that ERα-Δ AF2, a mutant estrogen receptor α (ERα) deleted for the C-terminal activation function 2 (AF2) core domain, directs estradiol (E ₂)-dependent repression and impairs E₂-induced transactivation by wild type ERα. This repression required coexpressed BRG1 in SW-13 cells that lack BRG1, the ATPase constituent of the chromatin-remodeling SWI·SNF complex, and was abolished by HDAC inhibitor trichostatin A. We further demonstrated that ERα-ΔAF2 constitutively associates with SMRT but binds DNA in an E₂-dependent manner in vivo. These results suggest that ERα-ΔAF2 and similar mutant receptors recently found associated with certain tumors may actively perturb the normal E₂ signaling via SWI/SNF, N-CoR/SMRT, and HDAC.