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

Javier A. Menendez, Adriana Papadimitropoulou, Luciano Vellon, Ruth Lupu

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2425-2432
Number of pages8
JournalEuropean Journal of Cancer
Volume42
Issue number15
DOIs
StatePublished - Oct 2006
Externally publishedYes

Fingerprint

Mediterranean Diet
Monounsaturated Fatty Acids
Oleic Acid
Oncogenes
Ovarian Neoplasms
Stomach Neoplasms
erbB-2 Genes
Transcription Factors
Binding Sites
Breast Neoplasms
DNA
Neoplasms
Genes
Proteins
Gene Amplification
Tumor Cell Line
Luciferases
Transfection
Up-Regulation
Complementary DNA

Keywords

  • Cancer
  • erbB-2
  • Her-2/neu
  • Mediterranean diet
  • Oleic acid
  • Olive oil
  • PEA3

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

Cite this

@article{ef302625de70431c9b4276fbf7c7ed89,
title = "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",
abstract = "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.",
keywords = "Cancer, erbB-2, Her-2/neu, Mediterranean diet, Oleic acid, Olive oil, PEA3",
author = "Menendez, {Javier A.} and Adriana Papadimitropoulou and Luciano Vellon and Ruth Lupu",
year = "2006",
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T1 - A genomic explanation connecting "Mediterranean diet", olive oil and cancer

T2 - 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

AU - Menendez, Javier A.

AU - Papadimitropoulou, Adriana

AU - Vellon, Luciano

AU - Lupu, Ruth

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AB - 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.

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