Abstract
Estrogen antagonists are universally employed in the breast cancer therapy, although antagonist therapy is limited by the inevitable development of cellular resistance. The molecular mechanisms by which these agents inhibit cellular proliferation in breast cancer cells are not fully defined. Recent studies have shown the involvement of the E2F pathway in tamoxifen-induced growth arrest. We show that an E2F repressor, prohibitin, and the chromatin modifiers Brg1/Brm are required for estrogen antagonist-mediated growth suppression through the estrogen receptor, and that their recruitment to native promoter-bound E2F is induced via a JNK1 pathway. In addition, we demonstrate major mechanistic differences among the signaling pathways initiated by estrogen, estrogen deprivation, and estrogen antagonists. Collectively, these findings suggest that the prohibitin/Brg1/Brm node is a major cellular target for estrogen antagonists, and thereby also implicate prohibitin/Brg1/Brm as potentially important targets for breast cancer therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Anthracenes / pharmacology
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chromatin / metabolism
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Chromatin Immunoprecipitation
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DNA Helicases
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Enzyme Inhibitors / pharmacology
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Estrogen Antagonists / pharmacology
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Female
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Flow Cytometry
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G1 Phase
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Gene Expression Regulation / drug effects*
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Humans
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Immunoblotting
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Luciferases / metabolism
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Mitogen-Activated Protein Kinase 8 / drug effects
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Mitogen-Activated Protein Kinase 8 / metabolism
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Nuclear Proteins / metabolism*
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Precipitin Tests
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Prohibitins
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RNA, Small Interfering / metabolism
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Receptors, Estrogen / agonists
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Receptors, Estrogen / genetics*
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Repressor Proteins / metabolism
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Repressor Proteins / pharmacology*
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Tamoxifen / analogs & derivatives*
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Tamoxifen / pharmacology
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Transcription Factors / metabolism*
Substances
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Anthracenes
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Antineoplastic Agents
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Chromatin
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Enzyme Inhibitors
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Estrogen Antagonists
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Nuclear Proteins
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Prohibitins
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RNA, Small Interfering
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Receptors, Estrogen
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Repressor Proteins
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Transcription Factors
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Tamoxifen
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afimoxifene
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pyrazolanthrone
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Luciferases
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Mitogen-Activated Protein Kinase 8
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SMARCA4 protein, human
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DNA Helicases