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

Departments of ¹ Pathology and ² Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina and ³ LifeCell Corp., Branchburg, New Jersey

Requests for reprints: Iris J. Edwards, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157. Phone: 336-716-2677; E-mail: iedwards{at}wfubmc.edu.

Key Words: Breast cancer • Cellular, molecular, and tumor biology • Effectors of apoptosis • Natural products • Experimental and molecular therapeutics

Diets enriched in n-3 polyunsaturated fatty acids (n-3 PUFA) may protect against breast cancer but biochemical mechanisms are unclear. Our studies showed that the n-3 fatty acid docosahexaenoic acid (DHA) up-regulated syndecan-1 (SDC-1) in human breast cancer cells, and we tested the hypothesis that DHA-mediated up-regulation of SDC-1 induces apoptosis. DHA was delivered to MCF-7 cells by n-3 PUFA–enriched low-density lipoproteins (LDL) or by albumin in the presence or absence of SDC-1 small interfering RNA. The n-3 PUFA induced apoptosis, which was blocked by SDC-1 silencing. We also confirmed that SDC-1 up-regulation and apoptosis promotion by n-3 PUFA was mediated by peroxisome proliferator-activated receptor (PPAR). Using a luciferase gene driven by either a PPAR response element or a DR-1 site present in the SDC-1 promoter, reporter activities were enhanced by n-3 LDL, DHA, and PPAR agonist, whereas activity of a luciferase gene placed downstream of a mutant DR-1 site was unresponsive. Cotransfection with dominant-negative PPAR DNA eliminated the increase in luciferase activity. These data provide strong evidence that SDC-1 is a molecular target of n-3 PUFA in human breast cancer cells through activation of PPAR and that n-3 PUFA–induced apoptosis is mediated by SDC-1. This provides a novel mechanism for the chemopreventive effects of n-3 PUFA in breast cancer. [Cancer Res 2008;68(8):2912–9]