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 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Cell Cycle / drug effects
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Cell Cycle / physiology
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / physiology*
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Cell Division / drug effects
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Cell Division / physiology
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Cyclin-Dependent Kinase Inhibitor p27
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DNA-Binding Proteins / metabolism
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Estradiol / analogs & derivatives*
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Estradiol / pharmacology
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Estrogen Receptor Modulators / pharmacology*
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Estrogen Receptor alpha
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Fulvestrant
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Growth Substances / pharmacology*
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Humans
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Nuclear Proteins / metabolism
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Nuclear Receptor Co-Repressor 1
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Nuclear Receptor Co-Repressor 2
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Receptors, Estrogen / metabolism
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Repressor Proteins / metabolism
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Selective Estrogen Receptor Modulators / pharmacology*
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Tamoxifen / analogs & derivatives
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Tamoxifen / pharmacology*
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Transduction, Genetic
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Tumor Cells, Cultured
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology*
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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Estrogen Receptor Modulators
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Estrogen Receptor alpha
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Growth Substances
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NCOR1 protein, human
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NCOR2 protein, human
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Nuclear Proteins
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Nuclear Receptor Co-Repressor 1
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Nuclear Receptor Co-Repressor 2
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Receptors, Estrogen
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Repressor Proteins
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Selective Estrogen Receptor Modulators
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Tumor Suppressor Proteins
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Tamoxifen
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Cyclin-Dependent Kinase Inhibitor p27
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afimoxifene
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Fulvestrant
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Estradiol