Abstract 5552: New models for prostate and colon carcinogenesis in PhIP-treated hCYP1A mice

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The food mutagen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine(PhIP), is mainly metabolized by human CYP1A2 through N-CYP1A2 through N2-hydroxylation (activation) and by mouse Cyp1a2 through 4′-hydroxylation (detoxification). In order to mimic human PhIP carcinogenesis in mice, we treated hCYP1A mice (which express human CYP1A but not mouse Cyp1a) with PhIP by oral gavage. Following a dose of PhIP (200 mg/kg b.w.), low-grade prostate intraepithelial neoplasia (PIN) were observed after 20 weeks, high-grade PIN were observed after 30 weeks, and microinvasive carcinomas and adenocarcinomas in ventral, dorsolateral, and coagulating gland were observed after 40 and 50 weeks. Similar to human prostate carcinogenesis, higher than normal GSTP1 levels were observed in proliferative inflammatory atrophic lesions, and GSTP1 expression was lost in high-grade PIN and carcinomas. Under these experimental conditions, colon tumors were not observed. However, in mice that were treated with PhIP (200 mg/kg) and, a week later, followed by treatment with 1.5% dextran sodium sulfate (DSS) in drinking fluid for 1 week, colon tumors were observed after 6 weeks (with 85% tumor incidence and 3.75±0.70 tumors/mouse) and >90% of the tumors were adenocarcinomas. The tumors had overexpressed β-catenin, c-myc, cyclinD1, iNOS and COX-2. In parallel studies with wild type mice treated with PhIP, or PhIP plus DSS, only low-grade PIN, but no colon tumors, were observed. Experiments are ongoing to study the effects of high-fat diet and other dietary factors in modulating carcinogenesis. These models, when fully characterized, could be very useful experimental systems to study diet and prostate/colon cancer (supported by NIH grants CA120915 and CA120915-S2). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5552. doi:10.1158/1538-7445.AM2011-5552