N-3 fatty acids and lipid peroxidation in breast cancer inhibition

Long-chain n-3 fatty acids (FA) consistently inhibit the growth of human breast cancer (BC) cells both in culture and in grafts in immunosuppressed mice. Large cohort studies have, however, failed to confirm a protective effect for fish oils rich in n-3 FA against BC risk. The present review examines new evidence on biological mechanisms which may be involved in the inhibition of mammary carcinogenesis by long-chain n-3 FA, focusing on an apoptotic effect by its lipid peroxidation products. Dietary intake of n-3 FA leads to their incorporation into cell membrane lipids. Increased apoptosis in human BC cells following exposure to long-chain n-3 FA such as eicosapentaenoic and docosahexaenoic acids is generally ascribed to their inhibition of cyclooxygenase 2 which promotes mammary carcinogenesis. In addition however, long-chain n-3 FA are particularly likely to activate peroxisome proliferator-activated receptor (PPAR)-gamma, a key regulator of lipid metabolism but also capable of modulating proliferative activity in a variety of cells including mammary cells. Expression of PPAR-gamma in the nucleus is activated by second messengers such as J series prostaglandins and the latter have been shown to cause apoptosis in vivo in explants of human BC cells in immunosuppressed mice. In mammary tumours, it is observed that long-chain FA not only increase apoptosis, but also increase lipid peroxidation, and the apoptotic effect can be reversed by antioxidants. The rationale for use of n-3 FA dietary supplements in counteracting BC progression needs to be tested clinically in a phase 2 pilot study, while at the same time, the effect on whole-body lipid peroxidation needs to be monitored. Dietary supplements of fish oil rich in n-3 FA are proposed for premenopausal women over the age of 40 years who are shown to be at increased BC risk. Biological markers in breast tissue of BC progression will be monitored, and observed changes related to serial plasma levels of isoprostanes as a measure of whole-body lipid peroxidation.