Short CommunicationA 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
Introduction
The relationship between olive oil intake and cancer risk has become a controversial issue that could have very important repercussions for human health. Different studies have shown that the consumption of olive oil may have a potential role in lowering the risk of malignant neoplasms, especially breast and stomach cancer; and also in ovary, colon and endometrium cancer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. However, the mechanisms by which the effects of olive oil are mediated are not well understood. One of the remaining concerns, before going for a causal interpretation of the inverse relation between olive oil intake and cancer risk, is to establish definitely if olive oil-related anti-cancer effects can be explained by its monounsaturated fatty acid (MUFA) content (i.e., high levels of the ω-9 MUFA oleic acid) or the antioxidant components of the unsaponifiable fraction 11.
Since cancer development and progression is believed to be a multi-step process, we recently hypothesized that a novel molecular explanation for the anti-cancer actions of olive oil may relate to the ability of oleic acid (OA; 18:1n − 9) to specifically regulate key cancer-related oncogenes 12. Supporting our hypothesis, exogenous supplementation of cultured breast cancer cells with OA was found to significantly down-regulate the expression of Her-2/neu 13, a well-characterized oncogene (also called neu or erbB-2) that plays a key role in the etiology, progression and chemosensitivity of various types of human cancer 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26. These anti-Her-2/neu properties of OA offered a previously unknown molecular mechanism by which olive oil may regulate the malignant behavior of breast cancer cells. These findings generated intense public interest, since no toxicities have been reported or suspected with OA, and suggested that supplementation with OA may represent a promising dietary intervention for the prevention and/or management of Her-2/neu-related breast carcinomas 27, 28. However, two major questions remained to be addressed: (1) What is the molecular mechanism linking tumour cells’ response to OA and Her-2/neu gene expression? and (2) Is the ability of OA to down-regulate Her-2/neu a common mechanism relevant to other types of cancer other than breast cancer?
Although overexpression of Her-2/neu both in tumours and in derived cell lines was originally attributed solely to amplification of the erbB-2 gene (usually 2- to 10-fold), an elevation in Her-2/neu mRNA levels per gene copy is also observed in all the cell lines examined exhibiting gene amplification 29. This indicates that overexpression of the gene precedes and increases the likelihood of gene amplification. Indeed, an increase in transcription rate sufficient to account for the degree of overexpression has been shown in a number of Her-2/neu-overexpressing cancer cell lines 30. Our current experiments sought to characterize the effects of OA treatment on the transcription rate of Her-2/neu gene. We have also addressed if the ability of OA to down-regulate Her-2/neu is a common mechanism of OA action towards tumour types reported to exhibit Her-2/neu overexpression, including breast, ovarian and gastric carcinomas. We report that OA promoted the up-regulation of the potent trans-repressor of the human Her-2/neu gene promoter PEA3 and could account in part the ability of OA to suppress Her-2/neu overexpression in cancer cells. These findings represent a novel genomic explanation linking “Mediterranean diet” and cancer, as OA-induced transcriptional repression of Her-2/neu gene seems to equally operate in various types of human malignancies previously shown to be influenced by olive oil consumption such as breast, ovarian and stomach carcinomas.
Section snippets
Materials
Phenol red-containing improved minimal essential medium (IMEM) was from Biofluids (Rockville, MD, USA). Oleic acid (18:1n − 9) was purchased from Sigma Chemical Co. (St. Louis, Missouri, USA). The cultures were supplemented, where indicated, with fatty acid-free bovine serum albumin (FA-free BSA; 0.1 mg/ml) complexed with a specific concentration of OA. A BSA-OA concentrated (100×) solution was formed by mixing 1 ml BSA (10 mg/ml) with various volumes (1–10 μl) of OA (200 mg/ml) in ethanol. The
Exogenous supplementation with OA inhibits Her-2/neu gene promoter activity in breast, ovarian and stomach cancer cells
We used reporter gene expression analysis to characterize the effects of OA on Her-2/neu oncogene transcription. We performed transient transfection experiments with a luciferase reporter gene driven by the wild-type Her-2/neu promoter (p Nulit; Fig. 1, top panel). Exogenous supplementation with OA (20 μM; 24 h) was found to profoundly repress the activity of Her-2/neu gene promoter in SK-Br3 breast cancer cells (up to 56% inhibition; Fig. 1; bottom panel). Accordingly, a significant reduction on
Discussion
The observations reported in this study demonstrate that: (i) the PEA3 binding motif on the Her-2/neu promoter functions as a positive regulatory element for Her-2/neu gene transcription solely in cancer cells naturally exhibiting both Her-2/neu gene amplification and Her-2/neu protein overexpression (Fig. 3a); (ii) There is an inverse correlation between PEA3 and Her-2/neu expression, with low PEA3 expression occurring in Her-2/neu-overexpressing cancer cells and high PEA3 expression occurring
Conflict of interest statement
None declared.
Acknowledgments
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
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