Estrogen receptor alpha (ER alpha), a ligand controlled transcription factor, plays an important role in breast cancer growth and endocrine therapy. Tamoxifen (TAM) antagonizes ER alpha activity and has been applied in breast cancer treatment. TAM-bound ER alpha associates with nuclear receptor-corepressors. Mitogen-activated protein kinase (MAPK) has been elucidated to result in cross-talk between growth factor and ER alpha. mediated signaling. We show that activated MAPK represses interaction of TAM-bound ER alpha with silencing mediator for retinoid and thyroid hormone receptors (SMRT) and inhibits the recruitment of SMRT by ER alpha to certain estrogen target genes. Blockade of MAPK signaling cascade with MEK inhibitor U0126 promotes the interaction and subsequently inhibits ER alpha activity via enhanced recruitment of SMRT, leading to reduced expression of ER alpha target genes. The growth rate of MCF-7 cells was decelerated when treated with both TAM and U0126. Moreover, the growth of MCF-7 cells stably expressing SMRT showed a robust repression in the presence of TAM and U0126. These results suggest that activated MAPK signaling cascade attenuates antagonist-induced recruitment of SMRT to ER alpha, suggesting corepressor mediates inhibition of ER alpha trans-activation and breast cancer cell growth by antagonist. Taken together, our finding indicates combination of antagonist and MAPK inhibitor could be a helpful approach for breast cancer therapy. (C) 2010 Elsevier Inc. All rights reserved.