EM-800, a Novel Antiestrogen, Acts as a Pure Antagonist of the Transcriptional Functions of Estrogen Receptors and

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Abstract
Estrogens act as potent mitogens in a large number of breast cancers, and the use of estrogen receptor (ER) antagonists is, there- fore, considered the endocrine therapy of choice in the management of this disease. We describe the molecular properties of EM-652, the active metabolite of EM-800, a novel nonsteroidal antiestrogen com- pound, on the transcriptional functions of ERa and ERb. Using RT-PCR, we show that ERa and ERb are expressed in mouse mam- mary glands, suggesting that both receptors should be considered putative targets for antiestrogen action in the breast. In cotransfec- tion assays using a synthetic estrogen-responsive promoter, EM-652 shows no agonistic activity on ERa and ERb transcriptional function and blocks the estradiol (E2)-mediated activation of both ERa and ERb. EM-652 is also very effective in abrogating E2-stimulated ERa and ERb trans-activation of the pS2 promoter in HeLa cells. EM-652 does not alter binding of ERa and ERb to DNA. The Ras-mediated induction of ERa and ERb transcriptional activity in the presence of E2 is also completely abolished by EM-652. In addition, EM-652 blocks the E2-dependent activation of ERa and ERb by the steroid hormone receptor coactivator-1 as well as the in vitro interaction between SRC-1 and the ligand-binding domains of both ERs. These results demonstrate that the novel antiestrogen EM-800 fully impedes AF-1 and AF-2 activities of ERa and ERb and can, therefore, be considered a potent and pure antagonist of both ER subtypes. (Endocrinology 139: 111-118, 1998)

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