Hormonal Induction Mouse Models of Prostate Cancer

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DESCRIPTION (provided by applicant): This proposal is in response to PA-08-055, "Cancer Prevention Research Small Grant Program (R03)", proposing pilot-feasibility studies that address the development of innovative animal models to mimic the human [prostate] cancer process in order to expedite research in cancer prevention. Animal models of prostate carcinogenesis are essential in the development of chemopreventive agents. Only two models have been used to screen agents in a systematic fashion, the MNU (methylnitrosourea) plus testosterone rat model and the C3(1)-probasin-SV40-large T antigen transgenic mouse model, but neither model is ideal. There is clearly a need for additional models, particularly mouse models that recapitulate the various stages of human prostate cancer development and involve androgen action as human prostate carcinogenesis does. Mouse models have several major advantages over rat models, including their lower cost, the much smaller amounts of chemoprevention agents they require, and the potential to have shorter latent periods than those in rat models that typically require 12-13 months of treatment. These three issues have seriously impaired chemoprevention efficacy testing in animal models of prostate cancer. We propose here to test the hypothesis that two different experimental strategies for induction of prostate cancer that have been demonstrated to work in rats can be successfully applied to mice. These strategies include one model that has been used most extensively in preclinical chemoprevention efficacy testing, namely the MNU (methylnitrosourea) plus testosterone rat model. The other rat model, which entirely depends on steroid hormone action and involves oxidative stress mechanisms, is the so-called NBL (or Noble) rat model involving combined exposure to estradiol and testosterone. We propose to translate the steroid hormone prostate cancer induction approaches of the NBL and MNU plus testosterone rat models to mice. If successfully yielding a hormonally-induced prostate carcinogenesis mouse model, this will pave the way for R01-type and other grant applications applying this model (1) to identify efficacious prostate cancer chemoprevention agents and (2) to tests specific mechanistic hypotheses genetically modified mice treated with steroid hormones. The specific aims of the project are to determine whether prostate carcinomas and/or lesions comparable to human prostatic intraepithelial neoplasia (PIN) can be induced in mice by (1) MNU plus testosterone and (2) estradiol plus testosterone. The mouse models arising from this project may be well suited for the evaluation of chemopreventive activity of new candidate agents including antioxidants. Both approaches may also lead to development of new mouse models of prostate carcinogenesis for mechanistic research.