Abstract 949: Different lineages of carcinogenesis in prostate lobes in the transgenic adenocarcinoma of mouse prostate (TRAMP) model in C57BL/6 background and their responses to chemopreventive selenium

The transgenic adenocarcinoma of the mouse prostate (TRAMP) model is based on probasin promoter-driven expression of SV40 T-antigen (Tag) to inactivate p53 and Rb tumor suppressor to propel proliferative lesions and aggressive cancers in the prostate. The genetic background of mice (FVB vs. C57BL/6) has been known to profoundly affect the pathogenesis profiles and disease severity. A recent study suggested prostate lobe specificity of neuro-endocrine (NE) carcinomas vs. glandular epithelial lesions, challenging the classical notion of single-lineage disease progression from early epithelial lesions to poorly differentiated carcinomas. Because of the increasing use of this model for chemoprevention studies, it is critical to further characterize the lobe-specificity of lesion lineages in the prostate and determine their responses to chemopreventive agents. To this end, we carefully dissected the dorsolateral (DLP) and ventral prostate (VP) and macroscopic tumors from 30 male C57BL/6 TRAMP mice at 24-weeks of age and fixed tissues in 10% formalin for pathology diagnosis. Our results show that macroscopic tumors were Tag + , synaptophysin (Syp) + , androgen-receptor (AR) − and E-cadherin − NE carcinomas (poorly differentiated carcinomas) and were dissected exclusively from VP, not DLP. Lesions identified in lymph node, liver or lung of such NE-carcinoma bearing mice showed concordant patterns of biomarkers with the primary prostate NE-carcinomas and represent their metastases. In the DLP, we found lesions ranging from mild (formerly as low grade PIN), moderate to atypical hyperplasia of Tag (formerly as moderately differentiated adenocarcinoma) with Tag + , AR + and E-cadherin + expression and no NE-carcinoma. For assessing the impact of selenium on the long term survival from different lineages of prostate lesions, we analyzed archival tissues from a survival study published recently (Wang et al, Cancer Prev Res 2009): TRAMP mice received a daily oral dose of 3 mg Se/kg body weight as methylseleninic acid (MSeA) beginning at 10 weeks (n=31) or 16 weeks of age (n=30), or water (n=31) until euthanasia or 50 weeks of age. MSeA supplementation significantly delayed death from NE-carcinomas (30% life-time incidence). MSeA also prolonged survival of mice with enlarged seminal vesicle containing epithelial-stromal tumors that were Tag + , Syp − , E-cadherin + and AR +/low in the older TRAMP mice (>30 weeks). Interestingly, mice with enlarged seminal vesicle often had normal sized prostate. In summary, the C57BL/6 TRAMP mouse model represents two lineages of prostate carcinogenesis with an involvement of seminal vesicle tumorigenesis in older mice. Future chemoprevention studies should incorporate this new knowledge for efficacy assessment and for molecular target validations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 949.