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Cell Cycle Progression Stimulated by Tamoxifen-Bound Estrogen Receptor- and Promoter-Specific Effects in Breast Cancer Cells Deficient in N-CoR and SMRT

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Myles Brown, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, D730, Boston, Massachusetts 02115. E-mail: myles_brown{at}dfci.harvard.edu.

Estrogen receptor (ER) mediates the effects of estrogens in breast cancer development and growth via transcriptional regulation of target genes. Tamoxifen can antagonize ER activity and has been used in breast cancer therapy. Tamoxifen-bound ER 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 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 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 function and cell proliferation.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Coregulators:   NCOR  |  SMRT

Ligands:   all-trans-Retinoic acid  |  17β-Estradiol

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