Lobe‐specific lineages of carcinogenesis in the transgenic adenocarcinoma of mouse prostate and their responses to chemopreventive selenium

Abstract

The transgenic adenocarcinoma of mouse prostate (TRAMP) model is by far the most practical transgenic model for preclinical prostate cancer chemoprevention studies. It is critical to characterize the prostate lobe-specificity of lesion lineages to consolidate the advantages of this model and minimize its limitations for chemoprevention studies. We dissected dorsolateral (DLP), ventral (VP), and anterior prostate (AP) lobes, and macroscopic tumors from 90 male C57BL/6J TRAMP mice at 22-24 weeks of age (WOA) and analyzed lesions by histological, biochemical and proteomic approaches. To determine whether methylseleninic acid (MSeA) led to a deletion of initiated cells, we gave oral MSeA to TRAMP mice from 5 to 23 WOA or from 5 to 15 WOA and analyzed lesions at 23 WOA. All tumors (n = 18) were T-antigen(+), synaptophysin (SYP)(+), androgen-receptor(-), and E-cadherin(-) poorly differentiated neuroendocrine carcinomas (NE-Ca). They were traceable most frequently to VP (66.7%) and rarely to DLP (11.1%) and AP (5.6%) with an estimated life-time incidence of 1 out of 3 mice. In DLP, epithelial lesions ranged from mild-to-severe atypical hyperplasia, with T-antigen(+), SYP(-), androgen-receptor(+), and E-cadherin(+). Proteomic profiling revealed many molecular differences between VP and DLP. In MSeA experiment, 6 out of 19 (31.5%) mice developed NE-Ca in the control group, only 2 in each MSeA group of 17-18 mice (11.1-11.8%) bore a detectable NE-Ca. The C57BL/6J TRAMP mouse represents at least two lineages of prostate carcinogenesis. Chemoprevention studies should incorporate this knowledge for efficacy assessment and molecular target validations.