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Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611
The crystallization of the ligand-binding domain (LBD) of the estrogen receptor (ER) with 17ß-estradiol and raloxifene [A. M. Brzozowski et al., Nature (Lond.), 389: 753–758, 1997] now provides a molecular basis for the biological activity of complexes as either agonists or antagonists. It is well established that the critical structural feature of antiestrogens is a correctly positioned alkylaminoethoxy side chain. The X-ray crystallography clearly shows that the alkylaminoethoxy side chain of raloxifene causes a specific and inappropriate molecular perturbation of the LBD and that the nitrogen in the side chain must hydrogen bond with aspartate 351 in the LBD of ER.
We previously identified and characterized a naturally occurring mutation in the ER from a tamoxifen-stimulated transplantable human breast tumor line. The mutation is at AA351 of LBD, where the aspartate is changed to tyrosine (Asp351Tyr).
In this report, we compared and contrasted the pharmacology of raloxifene to block or induce E2-stimulated increase in TGF-
mRNA in stable transfectants of ER-negative human breast cancer cells with the cDNAs from wild-type, mutant-amino acid (AA) 400 ER and mutant-AA 351 ER. Our results show that the mutation at AA 351 that replaces aspartate by tyrosine specifically changes the pharmacology of raloxifene from an antiestrogen to an estrogen. By contrast, a mutation at AA 400 does not, and the antiestrogenic properties of raloxifene are retained. These data and the fact that the nitrogen in the side chain must specifically interact with aspartate 351 makes this the key to the antiestrogenic activity of raloxifene.
1 These studies were supported by NIH Grant CA-56143 and by the continued generosity of the Lynn Sage Breast Cancer Foundation of Northwestern Memorial Hospital.
2 To whom requests for reprints should be addressed, at Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, 303 East Chicago Avenue, 8258 Olson Pavilion, Chicago, IL 60611. Phone: (312) 908-4148; Fax: (312) 908-1372.
Received 1/ 6/98. Accepted 3/ 4/98.
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