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Effect of Low-Fat Diet on Development of Prostate Cancer and Akt Phosphorylation in the Hi-Myc Transgenic Mouse Model

¹ Department of Urology and ² Department of Biostatistics, School of Medicine, ³ Department of Physiological Science, ⁴ Department of Pathology, ⁵ Division of Pediatric Endocrinology and Department of Pediatrics, University of California; and ⁶ Urology Section, Department of Surgery, Veterans Administration, Greater Los Angeles Healthcare System, Los Angeles, California

Requests for reprints: William J. Aronson, University of California at Los Angeles, Department of Urology, 66-124 Center for Health Sciences, Box 951738, Los Angeles, CA 90095-1738. Phone: 310-268-3446; Fax: 310-268-4858; E-mail: waronson{at}ucla.edu.

Key Words: Akt • low-fat diet • Myc mouse

This study evaluated the effect of dietary fat on prostate cancer development by using the Hi-Myc mouse transgenic prostate cancer model. Hi-Myc mice develop murine prostatic intraepithelial neoplasia (mPIN) as early as 2 to 4 weeks and invasive adenocarcinoma between 6 and 9 months due to the overexpression of human c-Myc in the mouse prostate. Three-week-old male Hi-Myc mice were placed on high-fat (HF; 42% Kcal) or low-fat (LF; 12% Kcal) diets, and equal caloric intake was maintained until euthanasia at 7 months. The number of mice that developed invasive adenocarcinoma at 7 months was 27% less in the LF diet group (12/28) compared with the HF diet group (23/33, P < 0.05). Epithelial cells in mPIN lesions in the LF group had a significantly lower proliferative index compared with epithelial cells in the HF group (21.7% versus 28.9%, P < 0.05). During the mPIN phase of carcinogenesis (4 months), the LF group had higher serum insulin-like growth factor (IGF) binding protein-1 levels (21.0 ± 8.9 ng/mL versus 3.2 ± 0.8 ng/mL, P < 0.05) relative to the HF group. Akt (Ser⁴⁷³) phosphorylation, Akt kinase activity, and phosphorylation of downstream targets of Akt in prostates were significantly reduced in the LF diet group compared with the HF group. We conclude that dietary fat reduction delays transition from mPIN to invasive cancer in this Myc-driven transgenic mouse model, possibly through suppression of the IGF-Akt pathway and decreased proliferation of mPIN epithelial cells. [Cancer Res 2008;68(8):3066–73]