Dietary (n-3) Polyunsaturated Fatty Acids Inhibit HER-2/neu-Induced Breast Cancer in Mice Independently of the PPAR[gamma] Ligand Rosiglitazone
2005
Yee, Lisa D. | Young, Donn C. | Rosol, Thomas J. | VanBuskirk, Anne M. | Clinton, Steve
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 [gamma] (PPAR[gamma]), a nuclear hormone receptor also expressed in breast cancer, hold potential as cancer prevention agents. PPAR[gamma] 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[gamma] 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.
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