Genomic instability-based transgenic models of prostate cancer

To develop animal models that represent the broad spectrum of human prostat e cancer, we created transgenic mice with targeted prostate-specific expres sion of two genes (EcoRI and c-fos) implicated in the induction of genomic instability. Expression of the transgenes was restricted to prostate epithe lial cells by coupling them to the tissue-specific, hormonally regulated pr obasin promoter (PB), The effects of transgene expression were examined his tologically in prostate sections at time points taken from 4 to 24 months o f age. The progressive presence of regions of mild-to-severe hyperplasia, l ow- and high-grade prostatic intra-epithelial neoplasia, and well-different iated adenocarcinoma was observed in both PBEcoRI lines but no significant pathology was detected in the PBfos line. Prostate tissue of PBEcoRI mice w as examined for expression of p53, proliferating cell nuclear antigen (PCNA ) and Ki67 at multiple time points. Although p53 does not appear to be muta ted, levels of PCNA and Ki67 are elevated and correlate with the severity o f the prostatic lesions. Overall, pre-neoplastic and neoplastic stages repr esented in the PBEcoRI model showed similarity to corresponding early stage s of the human disease. This genomic instability-based model will be used t o study the mechanisms involved in the early stages of prostate carcinogene sis and to investigate the nature of subsequent events necessary for the pr ogression to advanced disease.