Inhibition of MAP kinase promotes the recruitment of corepressor SMRT by tamoxifen-bound estrogen receptor alpha and potentiates tamoxifen action in MCF-7 cells.
Estrogen receptor alpha (ERalpha), a ligand controlled transcription factor, plays an important role in breast cancer growth and endocrine therapy. Tamoxifen (TAM) antagonizes ERalpha activity and has been applied in breast cancer treatment. TAM-bound ERalpha associates with nuclear receptor-corepressors. Mitogen-activated protein kinase (MAPK) has been elucidated to result in cross-talk between growth factor and ERalpha mediated signaling. We show that activated MAPK represses interaction of TAM-bound ERalpha with silencing mediator for retinoid and thyroid hormone receptors (SMRT) and inhibits the recruitment of SMRT by ERalpha to certain estrogen target genes. Blockade of MAPK signaling cascade with MEK inhibitor U0126 promotes the interaction and subsequently inhibits ERalpha activity via enhanced recruitment of SMRT, leading to reduced expression of ERalpha 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 ERalpha, suggesting corepressor mediates inhibition of ERalpha transactivation 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.
Hong
Wei
W
Department of Immunology, Tianjin Medical University, 300070 Tianjin, China. hongwei@tijmu.edu.cn
Chen
Linfeng
L
Li
Juan
J
Yao
Zhi
Z
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000494:pharmacology; D056985:Nuclear Receptor Co-Repressor 2 / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology*
D018931:Antineoplastic Agents, Hormonal; D002070:Butadienes; D047628:Estrogen Receptor alpha; C539130:NCOR2 protein, human; D009570:Nitriles; D056985:Nuclear Receptor Co-Repressor 2; D047428:Protein Kinase Inhibitors; C113580:U 0126; D013629:Tamoxifen; D020929:Mitogen-Activated Protein Kinase Kinases