afimoxifene and pyrazolanthrone

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.

Topics: Anthracenes; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Chromatin; Chromatin Immunoprecipitation; DNA Helicases; Enzyme Inhibitors; Estrogen Antagonists; Female; Flow Cytometry; G1 Phase; Gene Expression Regulation; Humans; Immunoblotting; Luciferases; Mitogen-Activated Protein Kinase 8; Nuclear Proteins; Precipitin Tests; Prohibitins; Receptors, Estrogen; Repressor Proteins; RNA, Small Interfering; Tamoxifen; Transcription Factors