BioWorld International Correspondent

LONDON - Oleic acid, the main component of olive oil, can directly reduce the expression of an oncogene that plays an important role in about a fifth of all breast cancers, a new study suggested.

The oncogene concerned, which encodes the protein Her-2/neu (also known as erbB-2), is the same one targeted by Genentech's monoclonal antibody treatment known as Herceptin (trastuzumab).

Remarkably, the study showed that when oleic acid was added to breast cancer cells at the same time as trastuzumab, the compounds acted synergistically to down-regulate expression of Her-2/neu and kill cancer cells.

Ramon Colomer, chief of medical oncology at the Institut Catala Oncologia in Girona, Spain, told BioWorld International: "The focus of our research is now going to be whether it is possible to improve the treatment of cancer patients by making dietary interventions. We want to know if a diet rich in olive oil can help make treatment with trastuzumab more effective, and whether it can delay the onset of resistance, which eventually develops in most patients."

The lead researcher on the study, Javier Menendez, assistant professor at the Northwestern University Feinberg School of Medicine in Chicago and a research scientist with the Evanston Northwestern Healthcare Research Institute, said: "Our findings underpin epidemiological studies that show that the Mediterranean diet has significant protective effects against cancer, heart disease and aging. To our knowledge, this is the first report that a dietary monounsaturated fatty acid previously suggested to be protective against breast cancer significantly down-regulates the expression of Her-2/neu."

Menendez and his colleagues reported the study in a paper in the Jan. 10, 2005, online edition of Annals of Oncology. The paper is titled "Oleic acid, the main monounsaturated fatty acid of olive oil, suppresses Her-2/neu (erbB-2) expression and synergistically enhances the growth inhibitory effects of trastuzumab (Herceptin) in breast cancer cells with Her-2/neu oncogene amplification."

The group now is planning to carry out a trial in women taking trastuzumab for breast cancer, to evaluate whether those eating a diet rich in olive oil survive longer than those who do not.

Trastuzumab was approved in 1998 and comprises monoclonal antibodies that bind to the Her-2/neu protein, which is overexpressed on the surface of cells in some breast cancers. Unfortunately, resistance to the therapy develops rapidly.

Colomer and his colleagues have been investigating the effects of dietary fatty acids on the impact of chemotherapy on cancer cells for some years. In an earlier study, they found that gamma-linoleic acid, as well as oleic acid, enhanced the action of the breast cancer drug Taxol. Two years ago, they observed that oleic acid likewise seemed to enhance the anticancer action of trastuzumab. "But we did not want to publish until we were absolutely certain about this effect and could establish the molecular mechanisms responsible for it," Colomer said.

The latest study was designed to explore in more detail the mechanism by which oleic acid achieved that result. The researchers added oleic acid to breast cancer cells that were overexpressing Her-2/neu oncogene. They found that there was a "dramatic" reduction of up to 46 percent in the amount of Her-2/neu on the surface of the cells.

When oleic acid was added at the same time as trastuzumab, the amount of Her-2/neu present on the surface of the cells fell by as much as 70 percent.

Experiments showed that oleic acid interacted synergistically with trastuzumab to promote apoptosis in breast cancer cells that overexpressed the Her-2/neu oncogene.

Writing in Annals of Oncology, Menendez and his colleagues reported that preliminary results strongly suggested that oleic acid represses transcription of Her-2/neu by up-regulating PEA3, a DNA-binding protein that previously has been shown to inhibit tumorigenesis promoted by Her-2/neu, by down-regulating the promoter of Her-2/neu.

They concluded: "Although caution must be applied when extrapolating in vitro results into clinical practice, these findings together present the concept that a higher level of oleic acid in breast tissue could provide an effective means of influencing the outcome of Her-2/neu-overexpressing breast cancer, a subset of breast carcinoma with poor prognosis. This previously unrecognized property of oleic acid will help us to understand the molecular mechanisms by which individual fatty acids such as oleic acid may regulate the malignant behavior of breast cancer cells."

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