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

Estrogens act as potent mitogens in a large number of breast cancers, and the use of estrogen receptor (ER) antagonists is, therefore, 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 compound, on the transcriptional functions of ERα and ERβ. Using RT-PCR, we show that ERα and ERβ are expressed in mouse mammary glands, suggesting that both receptors should be considered putative targets for antiestrogen action in the breast. In cotransfection assays using a synthetic estrogen-responsive promoter, EM-652 shows no agonistic activity on ERα and ERβ transcriptional function and blocks the estradiol (E2)-mediated activation of both ERα and ERβ. EM-652 is also very effective in abrogating E2-stimulated ERα and ERβ trans-activation of the pS2 promoter in HeLa cells. EM-652 does not alter binding of ERα and ERβ to DNA. The Ras-mediated induction of ERα and ERβ transcripti...

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