title: Omega-3 fatty acids induce apoptosis in human breast cancer cells and mouse mammary tissue through syndecan-1 inhibition of the MEK-Erk pathway.
abstract: 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.
authors.affiliation: Department of Pathology, Wake ForestUniversity School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Haiguo
authors.initials: H
authors.lastname: Sun
authors.forename: Yunping
authors.initials: Y
authors.lastname: Hu
authors.forename: Zhennan
authors.initials: Z
authors.lastname: Gu
authors.forename: Rick T
authors.initials: RT
authors.lastname: Owens
authors.forename: Yong Q
authors.initials: YQ
authors.lastname: Chen
authors.forename: Iris J
authors.initials: IJ
authors.lastname: Edwards
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000502:physiology; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D053668:Syndecan-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D014407:Tumor Cells, Cultured; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D015820:Cadherins; D053668:Syndecan-1; D051025:bcl-Associated Death Protein; C502406:fat1 protein, mouse; D004281:Docosahexaenoic Acids; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases