Differential SERM effects on corepressor binding dictate ERα activity in vivo

Selective estrogen receptor modulators (SERMs) show differential effects upon ERα activation function I (AF-1). Tamoxifen allows strong ERα AF-1 activity, whereas raloxifene allows less and ICI 182,780 (ICI) allows none. Here, we show that blockade of corepressor histone deacetylase (HDAC) activity reverses the differential inhibitory effect of SERMs upon AF-1 activity in MCF-7 cells. This suggests that differential SERM repression of AF-1 involves HDAC-dependent corepressors. Consistent with this, ICI and raloxifene are more potent than tamoxifen in promoting ERα-dependent sequestration of progesterone receptor-associated corepressors. Moreover, ICI and raloxifene are more efficient than tamoxifen in promoting ERα binding to the corepressor N-CoR in vivo and in vitro. An ERα mutation (537X) that increases N-CoR binding in the presence of all SERMs blocks AF-1 activity. An ERa mutation (L379R) that decreases N-CoR binding increases AF-1 activity in the presence of ICI and raloxifene and reverses the effect of the 537X mutation. The 537X and L379R mutations also alter the ligand preference of ERα action at AP-1 sites and C3 complement, an action that also involves AF-1. Together, our results suggest that differential SERM effects on corepressor binding can explain differences in SERM effects on ERα activity. We propose a model for differential effects of SERMs on N-CoR binding.