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Circumventing Tamoxifen Resistance in Breast Cancers Using Antiestrogens That Induce Unique Conformational Changes in the Estrogen Receptor¹

Departments of Pharmacology and Cancer Biology [C. E. C., J. D. N., D. P. M.], Biostatistics [G. B.], and Radiation Oncology [M. W. D.], Duke University, Durham, North Carolina 27710; GlaxoSmithKline, Research Triangle Park, North Carolina 27709 [T. M. W.]; and Bristol-Meyers Squibb, Princeton, New Jersey 08543-4000 [M. M. G.]

Tamoxifen inhibits estrogen receptor (ER) transcriptional activity by competitively inhibiting estradiol binding and inducing conformational changes in the receptor that may prevent its interaction with coactivators. In bone, the cardiovascular system, and some breast tumors, however, tamoxifen exhibits agonist activity, suggesting that the tamoxifen-ER complex is not recognized identically in all cells. We used phage display to demonstrate that the antiestrogen GW5638 induces a unique structural change in the ER. The biological significance of this conformational change was revealed in studies that demonstrated that tamoxifen-resistant breast tumor explants are not cross-resistant to GW5638. Because of these properties, this drug is currently being developed as a potential therapeutic for tamoxifen-resistant breast cancers.

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