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Human epidemiological studies have shown that diets enriched in n-3 polyunsaturated fatty acids (n-3 PUFA) are associated with a lower incidence of cancers including breast cancer. Our previous studies showed that the n-3 PUFA, docosahexaenoic acid (DHA), upregulated syndecan-1 (SDC-1) expression to induce apoptosis in the human breast cancer cell line MCF-7. We now present evidence of a signaling pathway that is impacted by SDC-1 in these cells and in mouse mammary tissues to result in apoptosis. In MCF-7 cells and SK-BR-3 cells, DHA and a SDC-1 ectodomain impaired signaling of the p44/42 mitogen-activated protein kinase (MAPK) pathway by inhibiting the phosphorylation of MAPK/Erk (MEK)/extracellular signal-regulated kinase (Erk) and Bad to induce apoptosis. SDC-1 siRNA significantly enhanced phosphorylation of these signal molecules and blocked the inhibitory effects of DHA on their phosphorylation. SDC-1 siRNA diminished apoptosis of MCF-7 cells, an effect that was markedly blocked by MEK inhibitor, PD98059. In vivo studies used (i) Fat-1 mice, a genetic model able to convert n-6 to n-3 PUFA to result in higher SDC-1 levels in Fat-1 mammary tissue compared with that of wild-type (wt) mice. Phosphorylation of MEK, Erk and Bad was lower in the Fat-1 versus wt tissue and (ii) SDC-1(-/-) mice that demonstrated markedly higher levels of phosphorylated MEK, Erk and Bad in mammary gland tissue compared with those of SDC(+/+) mice. These data elucidate a pathway whereby SDC-1, upregulated by DHA, induces apoptosis in breast cancer cells through inhibition of MEK/Erk/Bad signaling.

Omega-3 fatty acids induce apoptosis in human breast cancer cells and mouse mammary tissue through syndecan-1 inhibition of the MEK-Erk pathway