p27(Kip1) induces quiescence and growth factor insensitivity in tamoxifen-treated breast cancer cells.
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 alpha. 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 alpha 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.[1]References
- p27(Kip1) induces quiescence and growth factor insensitivity in tamoxifen-treated breast cancer cells. Carroll, J.S., Lynch, D.K., Swarbrick, A., Renoir, J.M., Sarcevic, B., Daly, R.J., Musgrove, E.A., Sutherland, R.L. Cancer Res. (2003) [Pubmed]
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