Up-regulation of acetyl-CoA carboxylase α and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells

Sarah Yoon, Min Young Lee, Sahng Wook Park, Jong Seok Moon, Yoo Kyung Koh, Yong Ho Ahn, Byeong Woo Park, Kyung Sup Kim

Research output: Contribution to journalArticle

138 Citations (Scopus)

Abstract

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 α (ACCα) 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 ACCα compared with MCF-7 and MDA-MB-231 breast cancer cells in which HER2 expression is low. The induction of FASN and ACCα 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 ACCα, and the HER2-mediated increase in ACCα 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 ACCα. On the other hand, FASN and ACCα 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 ACCα 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 ACCα in the breast cancer cells used in this study is translational regulation primarily through the mTOR signaling pathway.

Original languageEnglish
Pages (from-to)26122-26131
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number36
DOIs
Publication statusPublished - 2007 Sep 7

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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