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Silencing and Reactivation of the Selective Estrogen Receptor Modulator-Estrogen Receptor Complex¹

Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611 [H. L., E-S. L., A. D. L. R., V. C. J.]; Center for Breast Cancer, National Cancer Center, Koyang City Kyunggi-do, 4-11-351, Korea [E-S. L.]; and Signal Pharmaceuticals, San Diego, California 92121 [J. W. Z.]

4-Hydroxytamoxifen (4-OHT), a selective estrogen receptor modulator, is an agonist at a transforming growth factor- (TGF-) target gene in situ in MDA-MB-231 human breast cancer cells stably transfected with wild-type human ER. In contrast, raloxifene (Ral) is a complete antiestrogen silencing activation function (AF) 1 and AF2 in this system. A natural mutation D351YER enhances 4-OHT agonist activity and changes Ral-like compounds from antagonists to partial agonists. We reasoned that: either the conformation of the Ral-D351YER is altered, thereby reactivating AF2 in the ligand binding domain, or the change at amino acid 351 allosterically reactivates AF1 in the Ral-D351YER complex. Unlike the estradiol-ER complex, agonist activity of 4-OHT and raloxifene through ER and D351YER were not attributed to coactivator (such as SRC-1, AIB1) binding to the ligand binding domain. We conclude that the classic AF2 is not responsible for the agonist activities of 4-OHT-ER, 4-OHT-D351YER, and Ral-D351YER. To address the role of AF1, stable transfectants of ER or D351YER with an AF1 deletion (D351AF1, D351YAF1) were generated in MDA-MB-231 cells. Additionally, D538A/E542A/D545A triple mutations within helix 12 (D351–3m, D351Y3m) or the COOH-terminal 537 deletion (D351537) were tested. The agonist activities of 4-OHT and raloxifene were lost in these stable transfectants, but antiestrogenic action was retained. The reactivation of an estrogen-like property of the Ral-ER complex through AF1 with the D351Y mutation illustrates a novel allosteric mechanism for the selective estrogen receptor modulator ER complex.

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