n-3 Fatty acids and lipid peroxidation in breast cancer inhibition

Abstract

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, longchain n-3 FA are particularly likely to activate peroxisome proliferator-activated receptor (PPAR)-g, a key regulator of lipid metabolism but also capable of modulating proliferative activity in a variety of cells including mammary cells. Expression of PPAR-g 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.

Peroxisome Proliferator-Activated Receptor γ–Mediated Up-regulation of Syndecan-1 by n-3 Fatty Acids Promotes Apoptosis of Human Breast Cancer Cells

“…Biochemical mechanisms for the antitumor properties of n-3 PUFA are still unclear but may include changes in eicosanoid metabolism, reduction in oncogene expression, and modulation of lipid peroxidation (reviewed in refs. 12,13).…”

Breast cancer risk and erythrocyte compositions of n‐3 highly unsaturated fatty acids in Japanese

“…Especially, ecological studies have suggested that higher intake of fish rich in n-3 HUFAs is correlated with a lower cancer incidence in several sites. 4,5 Regarding suppression of carcinogenesis, n-3 HUFAs have been proposed to play critical roles in: (i) inhibition for biosynthesis of eicosanoids (e.g., prostaglandin E 2 ) via the arachidonic acid (AA, 20:4n-6) cascade 1,6 ; (ii) modulation of gene expression or the activities of signal transduction molecules involved in the control of cell growth, differentiation, apoptosis, angiogenesis and metastasis [7][8][9] ; (iii) estrogen metabolism 1 ; (iv) production of free radicals and reactive oxygen species; 7,8,10,11 (v) modulation of insulin sensitivity 1,12 and (vi) membrane fluidity. 1 For the AA cascade, such potential activities of EPA and DHA are estimated to be approximately 5 times higher than that of 18:3n-3.…”

Punicic acid is an ω-5 fatty acid capable of inhibiting breast cancer proliferation

“…Furthermore, there is evidence that mouse mammary tumors are more sensitive than normal tissues to the induction of reactive oxygen species-mediated apoptosis (33) and that developing tumors in vivo are inherently susceptible to dietinduced increased oxidative stress resulting in decreased tumor growth and progression (33,34). It has been proposed that the protective effect of dietary ˆ-3 fatty acids against mammary tumor development may be due to the presence of lipid peroxidation products arising from the peroxidation of -3 fatty acids (35). Therefore, reactive oxygen species may have dual roles whereby low levels result in normal protective signaling, intermediate levels lead to a variety of cellular damage promoting tumorigenesis and high levels could promote oxidative burst and cell death (reviewed in ref.…”