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Ligand-independent Activation of the Estrogen Receptors and ß by Mutations of a Conserved Tyrosine Can Be Abolished by Antiestrogens¹

Molecular Oncology Group, Royal Victoria Hospital, Montréal, Québec, H3A 1A1 Canada [G. B. T., A. T., V. G.]; Departments of Biochemistry, Medicine, and Oncology, McGill University, Montréal, Québec, H3G 1Y6 Canada [V. G.]; and Laboratory of Molecular Endocrinology, Centre Hospitalier de l'Université Laval Research Center, Québec, GIV 4G2 Canada [F. L.]

It has recently been suggested that mutation of a conserved tyrosine to asparagine within the ligand-binding domain of the estrogen receptor (ER) confers hormone-independent activation and insensitivity to antiestrogens (Q. X. Zhang et al., Cancer Res., 57: 1244–1249, 1997). In view of the recent discovery of ERß and the development of the novel nonsteroidal antiestrogen EM-800 and its active metabolite EM-652, we decided to reexamine this issue by introducing a series of mutations at the conserved tyrosine 537 in ER and 443 in ERß and measuring their transcriptional activity in the absence and presence of estradiol and the antiestrogens EM-652, ICI 182,780, and 4-hydroxytamoxifen. As demonstrated previously for ER, we observed that substituting a serine or asparagine but not a phenylalanine for the conserved tyrosine 443 in ERß confers constitutive transcriptional activity to the receptor. This activity was apparent on both the vitA2-ERE and the pS2 promoters in Cos-1 and HeLa cell lines as well as the human breast cancer cell line MDA-MB-231. However, the ligand-independent transcriptional activity of all ER and ERß mutants examined, including the tyrosine to asparagine substitutions, was completely abolished by the three antiestrogens tested in this system. Furthermore, hormone-independent interaction of ER and ERß mutant receptors with the steroid receptor coactivator-1 was abrogated by these antiestrogens. Our report, therefore, indicates that antiestrogens would be effective agents against constitutively active tyrosine ER and ERß mutants and suggests that this particular type of modified receptors are unlikely to contribute to resistance toward antiestrogens in breast cancer therapy.

¹ This work was supported by the Medical Research Council of Canada and the National Cancer Institute of Canada (to V. G.) and in part by a Medical Research Council of Canada Postdoctoral Fellowship (to G. B. T.) and a Scientist Scholarship (to V. G.). This work was supported in part by EndoRecherche, Inc.

² Equal contributions as first authors.

³ To whom requests for reprints should be addressed, at Molecular Oncology Group, Royal Victoria Hospital, 687 Pine Avenue West, Montréal, Québec, H3A 1A1 Canada. Phone: (514) 843-1479; Fax: (514) 843-1478; email: vgiguere@dir.molonc.mcgill.ca.

Received 12/ 1/97. Accepted 1/19/98.

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