Modeling Prostate Cancer by Conditional Gene Targeting

目前大多数前列腺癌转基因小鼠模型都有一个缺点，即启动癌基因（SV40 T抗原）在人类疾病的发病机制中没有已知的作用。因此，建立一种基于人类前列腺癌中常见的遗传病变的改进的小鼠前列腺癌模型是至关重要的。在前列腺癌细胞中观察到的两种最常见的染色体畸变包括8号染色体短臂上的序列丢失和8号染色体长臂上的序列增加。Nkx3.1是位于8p21的肿瘤抑制因子的强有力候选，它是一种含有同源盒的蛋白，在许多前列腺肿瘤和前列腺上皮内瘤变（PIN）病变中表达缺失。我们使用Cre/ loxp介导的重组产生了在成人前列腺中缺失Nkx3.1的小鼠。这些小鼠出现侵袭前PIN病变。Myc癌基因定位于8q24，是许多前列腺肿瘤扩增的靶标。Myc的过度表达在PIN病变、原发性癌和转移中逐渐增加，表明Myc的过度表达与肿瘤进展有关。有趣的是，在前列腺癌中，8q24的增加往往伴随着8p21的缺失，同时8p的缺失和8q的增加与患者预后不良有关。本提案的总体目标是在成年前列腺中产生并表征Nkx3.1条件缺失和Myc获得的小鼠。我们假设Nkx3.1的缺失和Myc的获得之间的合作将导致PIN病变进展为浸润性癌并最终转移性疾病。提出以下具体目的：1)通过Cre介导的前列腺重组产生并表征Myc的转基因小鼠。2)生成并表征Nkx3.1缺失和Myc在前列腺中过表达的小鼠。3)在这些模型中检查前列腺肿瘤发生中改变的遗传途径，特别强调已知在人类前列腺癌中普遍改变的途径。本研究旨在建立一种概括人类前列腺癌的体内遗传模型。这将为研究导致前列腺癌的分子事件提供一个重要的工具。

Most current transgenic mouse models of prostate cancer suffer from the drawback that the initiating oncogene (the SV40 T antigen) has no known role in the pathogenesis of the human disease. Thus it is critical to generate an improved murine model of prostate cancer that is based on the genetic lesions commonly observed in human prostate carcinoma. Two of the most common chromosomal aberrations observed in prostate carcinoma cells include loss of sequences from the short arm of chromosome 8 and gain of sequences on its long arm. A strong candidate for a tumor suppressor located at 8p21 is Nkx3.1, a homeobox- containing protein whose expression is lost in many prostate tumors and prostatic intraepithelial neoplasia (PIN) lesions. We have used Cre/loxP-mediated recombination to generate mice with deletion of Nkx3.1 in the adult prostate. These mice develop preinvasive PIN lesions. The Myc oncogene maps to 8q24, and is the target for amplification in many prostate tumors. Overrepresentation of Myc gradually increases in PIN lesions, primary carcinomas and metastases, indicating that Myc overexpression is associated with tumor progression. Intriguingly, gain of 8q24 is often accompanied by loss of 8p21 in prostate carcinomas, and concurrent loss of 8p and gain of 8q is associated with poor patient prognosis. The overall goal of this proposal is to generate and characterize mice with conditional loss of Nkx3.1 and gain of Myc in the adult prostate. We hypothesize that cooperation between loss of Nkx3.1 and gain of Myc will result in the progression of PIN lesions to invasive carcinoma and ultimately metastatic disease. The following Specific Aims are proposed: 1) To generate and characterize transgenic mice that overexpress Myc upon Cre- mediated recombination in the prostate. 2) To generate and characterize mice with concurrent loss of Nkx3.1 and overexpression of Myc in the prostate. 3) To examine the genetic pathways altered in prostate tumorigenesis in these models, with particular emphasis on pathways known to be commonly altered in human prostate carcinoma. This proposal seeks to develop an in vivo genetic model of prostate cancer that recapitulates the human disease. This will provide an important tool for studying the molecular events that lead to prostate cancer.