Hormonal Induction Mouse Models of Prostate Cancer

描述（由申请人提供）： 该提案是对PA-08-055“癌症预防研究小额资助计划（R 03）”的回应，该计划提出了试点可行性研究，旨在开发创新的动物模型来模拟人类[前列腺]癌症过程，以加快癌症预防研究。前列腺癌发生的动物模型在化学预防剂的开发中是必不可少的。只有两种模型被用于以系统的方式筛选药剂，MNU（甲基亚硝基脲）加睾酮大鼠模型和C3（1）-probasin-SV 40-大T抗原转基因小鼠模型，但两种模型都不理想。显然需要额外的模型，特别是小鼠模型，其概括了人类前列腺癌发展的各个阶段，并涉及雄激素作用，如人类前列腺癌发生一样。与大鼠模型相比，小鼠模型具有几个主要优势，包括其成本较低，所需的化学预防剂量少得多，并且与通常需要12-13个月治疗的大鼠模型相比，潜伏期可能更短。这三个问题严重损害了前列腺癌动物模型中的化学预防功效测试。我们建议在这里测试的假设，两种不同的实验策略，诱导前列腺癌，已被证明在大鼠中工作，可以成功地应用于小鼠。这些策略包括一种在临床前化学预防功效测试中使用最广泛的模型，即MNU（甲基亚硝基脲）加睾酮大鼠模型。另一种大鼠模型完全依赖于类固醇激素作用并涉及氧化应激机制，即所谓的NBL（或Noble）大鼠模型，涉及雌二醇和睾酮的联合暴露。我们建议将NBL和MNU加睾酮大鼠模型的类固醇激素前列腺癌诱导方法转化为小鼠。如果成功地产生经尿道诱导的前列腺癌发生小鼠模型，这将为R 01型和其他资助申请铺平道路，这些申请应用该模型（1）鉴定有效的前列腺癌化学预防剂和（2）测试用类固醇激素治疗的遗传修饰小鼠的特定机制假设。该项目的具体目的是确定（1）MNU+睾酮和（2）雌二醇+睾酮是否可以在小鼠中诱导前列腺癌和/或与人前列腺上皮内瘤（PIN）相当的病变。该项目产生的小鼠模型可能非常适合评估包括抗氧化剂在内的新候选药物的化学预防活性。这两种方法也可能导致新的小鼠模型的前列腺癌的机制研究的发展。

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.