TY - JOUR
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
N1 - Funding Information:
The authors thank Prof. Mien-Chie Hung (The University of Texas M.D. Anderson Cancer Center, Department of Cancer Biology, Section of Molecular Cell Biology, Houston, Texas, USA) for kindly providing Her-2/neu promoter constructs and MCF-7/Her2-18 cells. This work was supported by the Basic, Clinical and Translational Award (BRCTR0403141) from the Susan G. Komen Breast Cancer Foundation (USA), the Breast Cancer Concept Award (BC033538) from the Department of Defense (DOD, USA) and the Special Program For Research Excellence in Breast Cancer Career Development Awards P50CA89018-03 to JAM and by a RO1-Project of the Special Program For Research Excellence in Breast Cancer Career Development awards to R.L.
PY - 2006/10
Y1 - 2006/10
N2 - 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.
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.
KW - Cancer
KW - Her-2/neu
KW - Mediterranean diet
KW - Oleic acid
KW - Olive oil
KW - PEA3
KW - erbB-2
UR - http://www.scopus.com/inward/record.url?scp=33744780262&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33744780262&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2005.10.016
DO - 10.1016/j.ejca.2005.10.016
M3 - Article
C2 - 16406575
AN - SCOPUS:33744780262
SN - 0959-8049
VL - 42
SP - 2425
EP - 2432
JO - European Journal of Cancer
JF - European Journal of Cancer
IS - 15
ER -