Transgenic mouse with human mutant p53 expression in the prostate epithelium

Abstract

Background Apoptosis is disrupted in prostate tumor cells, conferring a survival advantage. p53 is a nuclear protein believed to regulate cancer progression, in part by inducing apoptosis. To test this possibility in future studies, the objective of the present study was to generate a transgenic mouse model expressing mutant p53 in the prostate (PR). Methods Transgene incorporation was tested using Southern analysis. Expression of mutant p53 protein was examined using immunofluorescence microscopy. Apoptosis in the PR was evaluated using the Tunnel method. Results A construct, consisting of the rat probasin promoter and a mutant human p53 fragment, was prepared and used to generate transgenic mice. rPB‐mutant p53 transgene incorporation, as well as nuclear accumulation of mutant human p53 protein, was demonstrated. Prostatic intraepithelial neoplasia (PIN) III and IV were found in PR of 52‐week old transgenic mice, whereas no pathological changes were found in the other organs examined. PR ability to undergo apoptosis following castration was reduced in rPB‐mutant p53 mice as compared to non transgenic littermates. Conclusions Transgenic rPB‐mutant p53 mice accumulate mutant p53 protein in PR, resulting in neoplastic lesions and reduced apoptotic potential in the PR. Breeding rPB‐mutant p53 mice with mice expressing an oncogene in their PR will be useful in examining interactions of multiple genes that result in progression of slow growing prostate tumors expressing oncogenes alone to metastatic cancer. © 2004 Wiley‐Liss, Inc.

Synergy of p53 and Rb Deficiency in a Conditional Mouse Model for Metastatic Prostate Cancer

“…According to earlier studies with mouse models, conditional inactivation of Rb or transgenic expression of mutant p53 results in development of prostatic hyperplasia and intraepithelial neoplasia (9,10), which is consistent with our data. However, contrary to our work, prostate epithelium-specific conditional knockout of p53 using PB-Cre4 mice did not result in any obvious phenotype by 18 months of age in one study (8).…”

“…Conditional inactivation of p53 does not lead to any neoplastic phenotype (8) whereas expression of the human mutant p53 results in prostatic intraepithelial neoplasia (PIN; ref. 9). Rb loss of function results in hyperplasia after Rb inactivation in situ (10) or carcinoma after transplantation of Rb-deficient cells as a prostatic graft (11).…”

Current mouse and cell models in prostate cancer research

“…Elgavish et al used a gene encoding a mutant p53, placed under the control of the rat probasin promoter to study the role of p53 mutations in PCa. The resulting transgenic mice exhibited HGPIN lesions (grade III-IV) by 52 weeks of age together with reduced apoptotic potential (Elgavish, et al 2004). …”

Modeling prostate cancer: a perspective on transgenic mouse models

“…Numerous transgenic models have been generated with tumor suppressor genes, p53 and retinoblastoma (Rb), as the primary candidates. A gene encoding a mutant p53 was placed under the control of the rat probasin promoter, and the resulting transgenic mice exhibited HGPIN lesions (grade III-IV) by 52 weeks of age together with reduced apoptotic potential [97]. Targeted deletion of Rb showed that the conditional loss of even a single allele of this gene in the prostate epithelial cells causes focal hyperplasia, providing a model for studies of early stage PC [98].…”