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p27^Kip1 Induces Quiescence and Growth Factor Insensitivity in Tamoxifen-treated Breast Cancer Cells¹

Cancer Research Program, Garvan Institute of Medical Research, New South Wales 2010, Australia [J. S. C., D. K. L., A. S., B. S., R. J. D., E. A. M., R. L. S.] and Unité Mixte de Recherche Centre National de la Recherche Scientifique, Pharmacologie Cellulaire et Moléculaire, 92296 Châtenay-Malabry Cedex, France [J-M. R.]

Tamoxifen, a selective estrogen-receptor modulator, is effective in the treatment and prevention of breast cancer, but therapeutic resistance is common. Pure steroidal antiestrogens are efficacious in tamoxifen-resistant disease and, unlike tamoxifen, arrest cells in a state of quiescence from which they cannot reenter the cell cycle after growth factor stimulation. We now show that in hydroxytamoxifen-treated cells, transduction of the cell cycle inhibitor p27^Kip1 induces quiescence and insensitivity to growth stimulation by insulin/insulin-like growth factor I and epidermal growth factor/transforming growth factor . Furthermore, reinitiation of cell cycle progression by insulin/insulin-like growth factor I in hydroxytamoxifen-arrested cells involves dissociation of the corepressors nuclear receptor corepressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptor (SMRT) from nuclear estrogen receptor and redistribution to the cytoplasm, a process that is inhibited by mitogen-activated protein/extracellular signal-regulated kinase, but not phosphatidylinositol 3'-kinase, inhibitors. These data suggest that agents that up-regulate p27^Kip1 or inhibit growth factor signaling via the extracellular signal-regulated kinases should be tested as therapeutic strategies in tamoxifen-resistant breast cancer.

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