Cell cycle progression stimulated by tamoxifen-bound estrogen receptor-α and promoter-specific effects in breast cancer cells deficient in N-CoR and SMRT

Estrogen receptor alpha (ER alpha) mediates the effects of estrogens in breast cancer development and growth via transcriptional regulation of target genes. Tamoxifen can antagonize ER alpha activity and has been used in breast cancer therapy. Tamoxifen-bound ER alpha associates with nuclear receptor corepressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors ( SMRT) at certain target genes. Here we show the effects of reducing N-CoR and SMRT levels on the actions of estrogen and tamoxifen in breast cancer cells. Silencing both corepressors led to tamoxifen-stimulated cell cycle progression without activation of the ER alpha target genes c-myc, cyclin D1, or stromal cell-derived factor 1, which play a role in estrogen-induced proliferation. By contrast, expression of X-box binding protein 1 was markedly elevated in tamoxifen-treated cells in which N-CoR and SMRT had been silenced. The gain in cell cycle entry seen with tamoxifen when N-CoR and SMRT were silenced was dependent on ER alpha and not observed upon treatment with estradiol or epidermal growth factor. These results suggest that N-CoR and SMRT play an active role in preventing tamoxifen from stimulating proliferation in breast cancer cells through repression of a subset of target genes involved in ER alpha function and cell proliferation.