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Endocrinology Vol. 139, No. 1 111-118
Copyright © 1998 by The Endocrine Society

ARTICLES

EM-800, a Novel Antiestrogen, Acts as a Pure Antagonist of the Transcriptional Functions of Estrogen Receptors {alpha} and ß1

André Tremblay2, Gilles B. Tremblay2, Claude Labrie, Fernand Labrie and Vincent Giguère

Molecular Oncology Group, Royal Victoria Hospital (A.T., G.B.T., V.G.), the Departments of Biochemistry, Medicine, and Oncology, McGill University (V.G.), Montreal, Québec, Canada H3A 1A1; and the Laboratory of Molecular Endocrinology, CHUL Research Center (C.L., F.L.), Québec City, Québec, Canada G1V 4G2

Address all correspondence and requests for reprints to: Dr. Vincent Giguère, Molecular Oncology Group, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Québec, Canada H3A 1A1. E-mail: vgiguere{at}dir.molonc.mcgill.ca

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 ER{alpha} and ERß. Using RT-PCR, we show that ER{alpha} and ERß 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 ER{alpha} and ERß transcriptional function and blocks the estradiol (E2)-mediated activation of both ER{alpha} and ERß. EM-652 is also very effective in abrogating E2-stimulated ER{alpha} and ERß trans-activation of the pS2 promoter in HeLa cells. EM-652 does not alter binding of ER{alpha} and ERß to DNA. The Ras-mediated induction of ER{alpha} and ERß transcriptional activity in the presence of E2 is also completely abolished by EM-652. In addition, EM-652 blocks the E2-dependent activation of ER{alpha} and ERß 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 ER{alpha} and ERß and can, therefore, be considered a potent and pure antagonist of both ER subtypes.




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