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J. Biol. Chem., Vol. 282, Issue 36, 26122-26131, September 7, 2007

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Up-regulation of Acetyl-CoA Carboxylase and Fatty Acid Synthase by Human Epidermal Growth Factor Receptor 2 at the Translational Level in Breast Cancer Cells^*

Sarah Yoon¹, Min-Young Lee¹, Sahng Wook Park, Jong-Seok Moon, Yoo-Kyung Koh, Yong-Ho Ahn, Byeong-Woo Park, and Kyung-Sup Kim²

From the Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Science, Institute of Genetic Science, Center for Chronic Metabolic Disease Research and the Department of Surgery, Yonsei University, College of Medicine, 134 Shinchondong, Seodaemungu, Seoul 120-752, Korea

Expression of the HER2 oncogene is increased in 30% of human breast carcinomas and is closely correlated with the expression of fatty acid synthase (FASN). In the present study, we determined the mechanism by which FASN and acetyl-CoA carboxylase (ACC) could be induced by HER2 overexpression. SK-BR-3 and BT-474 cells, breast cancer cells that overexpress HER2, expressed higher levels of FASN and ACC compared with MCF-7 and MDA-MB-231 breast cancer cells in which HER2 expression is low. The induction of FASN and ACC in BT474 cells were not mediated by the activation of SREBP-1. Exogenous HER2 expression in MDA-MB-231 cells induced the expression of FASN and ACC, and the HER2-mediated increase in ACC and FASN was inhibited by both LY294002, a phosphatidylinositol 3-kinase inhibitor, and rapamycin, a mammalian target of rapamycin (mTOR) inhibitor. In addition, the activation of mTOR by the overexpression of RHEB in MDA-MB-231 cells increased the synthetic rates of both FASN and ACC. On the other hand, FASN and ACC were reduced in BT-474 cells by a blockade of the mTOR signaling pathway. These changes observed in their protein levels were not accompanied by changes in their mRNA levels. The 5'- and 3'-untranslated regions of both FASN and ACC mRNAs were involved in selective translational induction that was mediated by mTOR signal transduction. These results strongly suggest that the major mechanism of HER2-mediated induction of FASN and ACC in the breast cancer cells used in this study is translational regulation primarily through the mTOR signaling pathway.

Received for publication, April 4, 2007 , and in revised form, July 13, 2007.

^* This work was supported by Grant R13-2002-054-01002-0 from the Basic Research Program of the Korea Science and Engineering Foundation and a faculty research grant of Yonsei University College of Medicine for 2006. 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.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 822-2228-1676; Fax: 822-312-5041; E-mail: kyungsup59{at}yumc.yonsei.ac.kr.

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