Agonist-dependent repression mediated by mutant estrogen receptor alpha 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 ER alpha-Delta AF2 a mutant estrogen receptor alpha (ER alpha) deleted for the C-terminal activation function 2 (AF2) core domain, directs estradiol (E-2)-dependent repression and impairs E-2-induced transactivation by wild type ER alpha. This repression required coexpressed BRG1 in SW-13 cells that lack BRG1, th e ATPase constituent of the chromatin-remodeling SWI-SNF complex, and was a bolished by HDAC inhibitor trichostatin A. We further demonstrated that ER alpha-Delta AF2 constitutively associates with SMRT but binds DNA in an E-2 -dependent manner in vivo. These results suggest that ER alpha-Delta AF2 an d similar mutant receptors recently found associated with certain tumors ma y actively perturb the normal E-2 signaling via SWI/SNF, N-CoR/SMRT, and HD AC.