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J. Biol. Chem., Vol. 278, Issue 44, 43363-43372, October 31, 2003

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Raloxifene Inhibits Estrogen-induced Up-regulation of Telomerase Activity in a Human Breast Cancer Cell Line^*

Jun Kawagoe, Masahide Ohmichi¶||, Toshifumi Takahashi, Chika Ohshima**, Seiji Mabuchi¶, Kazuhiro Takahashi, Hideki Igarashi, Akiko Mori-Abe, Maki Saitoh, Botao Du, Tsuyoshi Ohta, Akiko Kimura¶, Satoru Kyo, Masaki Inoue, and Hirohisa Kurachi

From the Department of Obstetrics and Gynecology and the ^**Division of Nursing, Yamagata University, School of Medicine, 2-2-2 Iidanishi, Yamagata 990-9585, Japan, the ^¶Department of Obstetrics and Gynecology, Osaka University Medical School, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan, and the Department of Obstetrics and Gynecology, Kanazawa University Medical School, 13-1, Takaramachi Kanazawa-shi, Ishikawa 920-8640, Japan

The mechanism by which raloxifene acts in the chemoprevention of breast cancer remains unclear. Because telomerase activity is involved in estrogen-induced carcinogenesis, we examined the effect of raloxifene on estrogen-induced up-regulation of telomerase activity in MCF-7 human breast cancer cell line. Raloxifene inhibited the induction of cell growth and telomerase activity by 17-estradiol (E2). Raloxifene inhibited the E2-induced expression of the human telomerase catalytic subunit (hTERT), and transient expression assays using luciferase reporter plasmids containing various fragments of the hTERT promoter showed that the estrogen-responsive element appeared to be partially responsible for the action of raloxifene. E2 induced the phosphorylation of Akt, and pretreatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, attenuated the E2-induced increases of the telomerase activity and hTERT promoter activity. Raloxifene inhibited the E2-induced Akt phosphorylation. In addition, raloxifene also inhibited the E2-induced hTERT expression via the PI3K/Akt/NFB cascade. Moreover, raloxifene also inhibited the E2-induced phosphorylation of hTERT, association of NFB with hTERT, and nuclear accumulation of hTERT. These results show that raloxifene inhibited the E2-induced up-regulation of telomerase activity not only by transcriptional regulation of hTERT via an estrogen-responsive element-dependent mechanism and the PI3K/Akt/NFB cascade but also by post-translational regulation via phosphorylation of hTERT and association with NFB.

Received for publication, April 25, 2003 , and in revised form, August 12, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Obstetrics and Gynecology, Yamagata University, School of Medicine, 2-2-2 Iidanishi, Yamagata 990-9585, Japan. Tel.: 81-23-628-5393; Fax: 81-23-628-5396; E-mail: masa{at}med.id.yamagata-u.ac.jp.

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