Olive oil is an integral ingredient of the "Mediterranean diet" and accumulating evidence suggests that it may have a potential role in lowering the risk of several types of cancers. The mechanisms by which the cancer-preventing effects of olive oil can be performed, however, are not known. We recently hypothesized that a novel molecular explanation concerning the anti-cancer actions of olive oil may relate to the ability of its monounsaturated fatty acid (MUFA) oleic acid (OA; 18:1n-9) to specifically regulate cancer-related oncogenes. Supporting our hypothesis, exogenous supplementation of cultured breast cancer cells with physiological concentrations of OA was found to suppress the overexpression of HER2 (Her-2/neu, erbB-2), a well-characterized oncogene playing a key role in the etiology, progression and response to chemotherapy and endocrine therapy in approximately 20% of breast carcinomas. OA treatment was also found to synergistically enhance the efficacy of trastuzumab, a humanized monoclonal antibody binding with high affinity to the ectodomain (ECD) of the Her2-coded p185(HER2) oncoprotein. Moreover, OA exposure significantly diminished the proteolytic cleavage of the ECD of HER2 and, consequently, its activation status, a crucial molecular event that determines both the aggressive behavior and the response to trastuzumab of Her2-overexpressing breast carcinomas. Our most recent findings further reveal that OA exposure may suppresses HER2 at the transcriptional level by up-regulating the expression of the Ets protein PEA3 -a DNA-binding protein that specifically blocks HER2 promoter activity- in breast, ovarian and stomach cancer cell lines. This anti-HER2 property of OA offers a previously unrecognized molecular mechanism by which olive oil may regulate the malignant behavior of cancer cells. From a clinical perspective, it could provide an effective means of influencing the outcome of Her-2/neu-overexpressing human carcinomas with poor prognosis. Indeed, OA-induced transcriptional repression of HER2 oncogene may represent a novel genomic explanation linking "Mediterranean diet", olive oil and cancer as it seems to equally operate in various types of Her-2/neu-related carcinomas.