p27Kip1 induces quiescence and growth factor insensitivity in tamoxifen-treated breast cancer cells

Jason S. Carroll, Danielle K. Lynch, Alexander Swarbrick, Jack Michel Renoir, Boris Sarcevic, Roger J. Daly, Elizabeth A. Musgrove, Robert L. Sutherland

Research output: Contribution to journalArticleResearchpeer-review

39 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4322-4326
Number of pages5
JournalCancer Research
Volume63
Issue number15
Publication statusPublished - 1 Aug 2003
Externally publishedYes

Cite this

Carroll, J. S., Lynch, D. K., Swarbrick, A., Renoir, J. M., Sarcevic, B., Daly, R. J., Musgrove, E. A., & Sutherland, R. L. (2003). p27Kip1 induces quiescence and growth factor insensitivity in tamoxifen-treated breast cancer cells. Cancer Research, 63(15), 4322-4326.