| Abstract
| - Tumor-associated fatty acid synthase (FAS) is implicated in tumorigenesis and connected to HER2(human epidermal growth factor receptor 2) by systemic analyses. Suppression of FAS in cancercells may lead to growth inhibition and cell apoptosis. Our previous study demonstrated that (−)-epigallocatechin 3-gallate (EGCG), the green tea catechin, could down-regulate FAS expression bysuppressing EGFR (epidermal growth factor receptor) signaling and downstream phosphatidylinositol3-kinase (PI3K)/Akt activation in the MCF-7 breast cancer cell line. Herein, we examined the effectsof EGCG on FAS expression modulated by another member of the erbB family, that is, HER2 orHER3. We identified that heregulin-β1 (HRG-β1), a HER3 ligand, stimulated dose-dependent FASexpression in breast cancer cell lines MCF-7 and AU565, but not MDA-MB-453. The time-dependentincrease in FAS expression after HRG-β1 stimulation was also observed in MCF-7 cells, and thisup-regulation was de novo RNA synthesis dependent. Treatment of MCF-7 cells with EGCG markedlyinhibited HRG-β1-dependent induction of mRNA and protein of FAS. EGCG also decreased thephosphorylation of Akt and extracellular signal-regulated kinase 1/2 that were demonstrated asselected downstream HRG-β1-responsive kinases required for FAS expression using dominant-negative Akt, PI3K inhibitors (LY294002 and wortmannin), or MEK inhibitor (PD98059). FAS inductionby HRG-β1 was also blocked by AG825, a selective HER2 inhibitor, and by genistein, a selectivetyrosine kinase inhibitor, indicating the formation of a heterodimer between HER2 and HER3, andtheir tyrosine kinase activities are essential for HRG-β1-mediated elevation of FAS. Additionally, growthinhibition of HRG-β1-treated cells was parallel to suppression of FAS by EGCG. Taken together,these findings extend our previous study to indicate that EGCG may be useful in the chemopreventionof breast carcinoma in which FAS overexpression results from HER2 or/and HER3 signaling. Keywords: (−)-Epigallocatechin 3-gallate (EGCG); heregulin-β1; fatty acid synthase (FAS); HER2; HER3;Akt; extracellular signal-regulated kinase1/2 (ERK1/2)
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