Complementary actions of docosahexaenoic acid and genistein on COX-2, PGE2 and invasiveness in MDA-MB-231 breast cancer cells.

N-3 polyunsaturated fatty acids (PUFA) and genistein have been associated with lowered cancer risk by reducing inflammatory prostanoids, cyclooxygenase-2 (COX-2) activity, and altering cell signaling. Few studies have investigated the effect of these compounds in combination on the molecular control of the COX-2 gene. In a series of experiments we examined a potential synchronous action of n-3 PUFA and genistein in down-regulating COX-2 expression to diminish prostaglandin E(2) (PGE(2)) production in MDA-MB-231 human breast cancer cells. Cells were treated with genistein and various PUFA including arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). PGE(2) concentrations, expression of COX-2, and cell invasiveness were determined. The n-3 PUFA and genistein alone lowered PGE(2) concentration, and genistein in combination with AA reversed the high level of this prostanoid in cell cultures enriched with AA. The degree of cell invasiveness was reversed by genistein in cell cultures treated with AA and further reduced in those given DHA. The n-3 PUFA, in contrast to AA, reduced COX-2 and NFkappaB expression. Genistein combined with AA reversed the effects of AA alone on the expression of COX-2 and NFkappaB. All three fatty acids increased the expression of PPARgamma in the cells only when combined with genistein. Our results support the premise that DHA and genistein exert complementary actions whilst genistein is antagonistic to AA for controlling PGE(2) production as well as invasiveness of MDA-MB-231 cells in culture by modulating the level of NFkappaB expression.