Molecular mechanism of action at estrogen receptor α of a new clinically relevant antiestrogen (GW7604) related to tamoxifen

Tamoxifen is the endocrine treatment of choice for all stages of estrogen receptor (ER)-positive breast cancer, and it is the first drug approved to reduce the incidence of breast cancer in high-risk women. Unfortunately, tamoxifen also possesses some estrogen-like effects in the uterus that cause a modest increase in the risk of endometrial cancer. GW5638 is a tamoxifen derivative with a novel carboxylic acid side chain with no uterotropic activity in the rat (Willson et al., J Med Chem, 1994, 37:1550–1552). We have compared and contrasted the actions of 4-hydroxytamoxifen (4-OHT, the active metabolite of tamoxifen) with GW7604 [the presumed metabolite of GW5638 in breast (MCF-7) and endometrial (ECC-1) cell lines in vitro]. GW7604 did not cause the growth of ECC-1 cells at any concentration (10−11–10−6 m), but 4-OHT was weakly estrogen-like at low concentrations (10−11–10−10 m). Compounds (10−7 m) blocked the growth promoting action of estradiol (10−10 m) in both ECC-1 and MCF-7 cells. Western blotting ...