A genomic explanation connecting "Mediterranean diet", olive oil and cancer: oleic acid, the main monounsaturated fatty acid of olive oil, induces formation of inhibitory "PEA3 transcription factor-PEA3 DNA binding site" complexes at the Her-2/neu (erbB-2) oncogene promoter in breast, ovarian and stomach cancer cells.
Olive oil is an integral ingredient of the "Mediterranean diet" and accumulating evidence suggests that it may have a potential role in lowering risk of several cancers. We recently hypothesized that the anti-cancer actions of olive oil may relate to its monounsaturated fatty acid (MUFA) oleic acid (OA; 18:1n-9) content to specifically regulate oncogenes. In this study, transient transfection experiments with human Her-2/neu promoter-driven luciferase gene established the ability of OA to specifically repress the transcriptional activity of Her-2/neu gene. Gene repression was seen in tumour-derived cell lines with Her-2/neu gene amplification and overexpression, including SK-Br3 (56% reduction), SK-OV3 (75% reduction) and NCI-N87 (55% reduction) breast, ovarian and stomach cancer cell lines, respectively. Also marginal decreases in promoter activity were observed in cancer cells expressing physiological levels of Her-2/neu (20% reduction in MCF-7 breast cancer cells). Remarkably, OA treatment in Her-2/neu-overexpressing cancer cells was found to induce up-regulation of the Ets protein polyomavirus enhancer activator 3 (PEA3), a transcriptional repressor of Her-2/neu promoter. Also, an intact PEA3 DNA-binding-site at endogenous Her-2/neu gene promoter was essential for OA-induced repression of this gene. Moreover, OA treatment failed to decrease Her-2/neu protein levels in MCF-7/Her2-18 transfectants, which stably express full-length human Her-2/neu cDNA controlled by a SV40 viral promoter. OA-induced transcriptional repression of Her-2/neu through the action of PEA3 protein at the promoter level may represent a novel mechanism linking "Mediterranean diet" and cancer.
Menendez
Javier A
JA
Department of Medicine, Evanston Northwestern Healthcare Research Institute, 1001 University Place, Evanston, IL 60201, and Department of Medicine, Northwestern University Feinberg, School of Medicine, Chicago, IL, USA.
Papadimitropoulou
Adriana
A
Vellon
Luciano
L
Lupu
Ruth
R
D001943:Breast Neoplasms / Q000235:genetics / Q000517:prevention & control; D045744:Cell Line, Tumor; D038441:Diet, Mediterranean; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D009369:Neoplasms / Q000235:genetics* / Q000517:prevention & control; D019301:Oleic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D000069463:Olive Oil; D010051:Ovarian Neoplasms / Q000235:genetics / Q000517:prevention & control; D010938:Plant Oils / Q000008:administration & dosage / Q000737:chemistry*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics / Q000517:prevention & control; D014157:Transcription Factors / Q000096:biosynthesis / Q000187:drug effects*
D019301:Oleic Acid; D000069463:Olive Oil; D010938:Plant Oils; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; C065788:transcription factor PEA3