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

Abstract

Expression of the HER2 oncogene is increased in ϳ30% 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.Because OA-519, a poor prognostic marker found in breast cancer cells, was shown to be a fatty acid synthase (FASN) 3 (1),a number of studies have demonstrated abnormally high levels of FASN in many human epithelial cancers and preneoplastic lesions (2, 3). FASN, a lipogenic enzyme, catalyzes the biosynthesis of palmitic acid that is used for the synthesis of triacylglycerol as a storage fuel molecule as well as membrane lipids including phospholipids and sphingolipids (4). In breast cancer cells, the expression of FASN is closely related to the aggressiveness of cancers as well as to the development, maintenance, and cell cycle progression of human cancers (5-7). Breast cancer cells that overexpress FASN undergo apoptosis when treated with small interfering RNAs (siRNAs) against FASN or FASN inhibitors, such as C75 and cerulenin (8 -11). Under physiological conditions, the activities of lipogenic enzymes, including FASN, are tightly regulated by nutritional and hormonal parameters at the transcription level. Sterol regulatory element-binding proteins (SREBP-1a, SREBP-1c, and SREBP-2) are the major transcription factors that mediate this regulation (12). SREBPs reside in endoplasmic reticulum membranes as inactive precursors. To become active, the NH 2 -terminal segments of SREBPs are released from the endoplasmic reticulum by proteolytic cleavage and enter the nucleus where they activate their target genes. SREBP-1 preferentially activates the genes in...

Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression

“…Indeed, it has been previously shown that the overexpression of FASN is most intense in carcinomas with higher risk of both disease recurrence and death, and steroid hormones, growth factors (EGFR, ERBB2), and the phosphatidylinositol-3 kinase (PI3K)-Akt signaling pathway regulate FASN expression (1,(27)(28)(29). There are also several publications showing the interconnection of FASN activity and HER2 signaling pathway (27,30,31). In the lipidomic and immunohistochemical analyses, we did not find major associations to the HER2 status, and thus our results challenge the earlier conceptions that HER2 signaling would have a major effect on the lipid metabolism (27).…”

Patuletin induces apoptosis of human breast cancer SK‑BR‑3 cell line via inhibiting fatty acid synthase gene expression and activity

“…The expression level of FASN is relatively low in the majority of normal tissues, however; increased expression of FASN has been identified in human breast cancer cells, particularly in SK-BR-3 cells (37). According to previous studies on tumor proliferation, FASN may contribute to the generation of tumor cell membranes (43).…”

De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy

“…Graner et al showed that the isopeptidase USP2a (ubiquitin-specific protease-2a) interacts with and stabilises FASN protein in prostate cancer (Graner et al, 2004). In breast cancer BT-474 cells that overexpress HER2, the expression of FASN and ACC are not mediated by SREBP-1, but by a mammalian target of rapamycin (mTOR)-dependent selective translational induction (Yoon et al, 2007). A significant copy number gain of FASN gene is also observed in prostate adenocarcinoma (Shah et al, 2006).…”