TY - JOUR
T1 - p27Kip1 induces quiescence and growth factor insensitivity in tamoxifen-treated breast cancer cells
AU - Carroll, Jason S.
AU - Lynch, Danielle K.
AU - Swarbrick, Alexander
AU - Renoir, Jack Michel
AU - Sarcevic, Boris
AU - Daly, Roger J.
AU - Musgrove, Elizabeth A.
AU - Sutherland, Robert L.
PY - 2003/8/1
Y1 - 2003/8/1
N2 - 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 p27Kip1 induces quiescence and insensitivity to growth stimulation by insulin/insulin-like growth factor I and epidermal growth factor/transforming growth factor α. 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 α 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 p27Kip1 or inhibit growth factor signaling via the extracellular signal-regulated kinases should be tested as therapeutic strategies in tamoxifen-resistant breast cancer.
AB - 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 p27Kip1 induces quiescence and insensitivity to growth stimulation by insulin/insulin-like growth factor I and epidermal growth factor/transforming growth factor α. 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 α 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 p27Kip1 or inhibit growth factor signaling via the extracellular signal-regulated kinases should be tested as therapeutic strategies in tamoxifen-resistant breast cancer.
UR - http://www.scopus.com/inward/record.url?scp=0042591471&partnerID=8YFLogxK
M3 - Article
C2 - 12907598
AN - SCOPUS:0042591471
SN - 0008-5472
VL - 63
SP - 4322
EP - 4326
JO - Cancer Research
JF - Cancer Research
IS - 15
ER -