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J. Biol. Chem., Vol. 282, Issue 42, 30535-30543, October 19, 2007

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Tamoxifen Induction of CCAAT Enhancer-binding Protein Is Required for Tamoxifen-induced Apoptosis^*

From the Department of Biochemistry, University of Illinois, Urbana, Illinois 61801

Low concentrations of tamoxifen or its active metabolite 4-hydroxytamoxifen (OHT) induce estrogen receptor (ER)-dependent apoptosis. To analyze the pathway of OHT-ER-induced apoptosis, we developed stably transfected lines of HeLa cells expressing wild-type ER and an inactive mutant ER unable to bind estrogen response elements. HeLa cells expressing the mutant ER and HeLa cells expressing wild-type ER in which the ER was knocked down with an ER-specific small interfering RNA were not killed by Tam or OHT, suggesting that estrogen response element-mediated transcription is required for Tam- and OHT-induced apoptosis. Microarray analysis to identify a gene(s) whose expression is important in OHT-ER-mediated apoptosis identified 19 mRNAs that OHT up-regulated by >1.6-fold and 15 down-regulated mRNAs. Gene function and the time course of induction by OHT-ER led us to further investigate CCAAT enhancer-binding protein (C/EBP), which has roles in cell cycle progression and apoptosis, and p21. Quantitative reverse transcription-PCR, Western blot analysis, and RNA interference knockdown suggest that cell cycle arrest resulting from OHT-ER induction of p21 may facilitate apoptosis. OHT-ER, but not E₂-ER, induced C/EBP mRNA and protein. RNA interference knockdown of C/EBP nearly abolished OHT-ER-induced apoptosis. We isolated stable cell lines that were resistant to OHT-induced apoptosis, contain full-length functional ER, and undergo apoptosis in response to etoposide. In these OHT-resistant cell lines both before and after OHT treatment, C/EBP levels are much lower than in OHT-sensitive cells. These studies establish a novel molecular site responsible for Tam- and OHT-ER-induced apoptosis of cancer cells.

Received for publication, June 12, 2007 , and in revised form, August 22, 2007.

^* This work was supported by National Institutes of Health Grants CA90371, HD16720, and DKO71909 and by a National Institutes of Health predoctoral traineeship (to D. Y.). 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.

This paper is dedicated to the memory of our late friend and colleague David Yu.

¹ Present address: Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 427 Maduan Street, Harbin 150001, China.

² To whom correspondence should be addressed: Dept. of Biochemistry, University of Illinois, 413 RAL, Box B4, 600 S. Mathews, Urbana, IL 61801. Tel.: 217-333-1788; Fax: 217-244-5858; E-mail: djshapir{at}uiuc.edu.

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