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

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