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Nutrition and Cancer

Dietary (n-3) Polyunsaturated Fatty Acids Inhibit HER-2/neu-Induced Breast Cancer in Mice Independently of the PPAR Ligand Rosiglitazone¹

Lisa D. Yee², Donn C. Young^*, Thomas J. Rosol, Anne M. VanBuskirk and Steven K. Clinton^**

Departments of Surgery, Division of Surgical Oncology, ^* Biostatistics, Veterinary Biosciences, and ^** Internal Medicine, Division of Hematology/Oncology, The Ohio State University, Columbus, OH 43210

²To whom correspondence should be addressed. E-mail: yee.52{at}osu.edu.

Overexpression of human epidermal growth factor receptor 2 (HER-2/neu) characterizes a molecular subtype of breast cancer associated with poor clinical outcome. Preventive strategies for HER-2/neu–positive breast cancer, which is often estrogen and progesterone receptor negative, remain undefined. Activators of peroxisome proliferator-activated receptor (PPAR), a nuclear hormone receptor also expressed in breast cancer, hold potential as cancer prevention agents. PPAR ligands include specific fatty acids and synthetic compounds, such as the thiazolidinediones, which appear to inhibit cell proliferation and tumorigenesis. We hypothesized that a thiazolidinedione, rosiglitazone, may serve as a chemopreventive agent for HER-2/neu-associated mammary carcinogenesis, but that efficacy may be influenced by dietary fat content. We studied the effects of diets enriched with corn or fish oil (25% of energy) with and without rosiglitazone (12 g/kg) in a 2 x 2 factorial design on mammary tumorigenesis in murine mammary tumor virus (MMTV)-HER-2/neu transgenic mice. Despite in vitro evidence of antiproliferative effects in an MMTV-HER-2/neu tumor cell line, rosiglitazone did not affect mammary carcinogenesis in vivo. Interestingly, fish oil–based diets markedly suppressed breast tumor incidence (57% of mice vs. 87% of corn oil–fed mice, P = 0.0001) as well as tumor multiplicity (P = 0.001) and mammary gland dysplasia (P = 0.001). These findings demonstrate a potent preventive effect of (n-3) PUFA on HER-2/neu–mediated mammary carcinogenesis, without interaction with a synthetic PPAR activator. Further studies focusing on the mechanisms by which (n-3) fatty acids suppress HER-2/neu signaling pathways involved in the pathogenesis of breast cancer are warranted.

KEY WORDS: • breast cancer • HER-2/neu • fatty acids • PPAR

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