Modeling Prostate Cancer by Conditional Gene Targeting

目前大多数前列腺癌转基因小鼠模型的缺点是启动癌基因(SV40T抗原)在人类疾病的发病机制中没有已知的作用。因此，以人类前列腺癌常见的遗传损伤为基础，建立一种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异常包括8号染色体短臂序列的丢失和长臂序列的获得。位于8p21的肿瘤抑制基因Nkx3.1是一个强有力的候选基因，它是一种含有同源盒的蛋白，在许多前列腺癌和前列腺上皮内瘤变(PIN)病变中都没有表达。我们已经使用Cre/loxP介导的重组来产生成年前列腺中Nkx3.1缺失的小鼠。这些小鼠会出现入侵前的PIN损害。Myc癌基因定位于8q24，是许多前列腺癌的扩增靶点。Myc在PIN皮损、原发癌和转移瘤中的过度表达逐渐增加，提示Myc过度表达与肿瘤的进展有关。有趣的是，在前列腺癌中，8q24的增加通常伴随着8p21的丢失，同时8p的丢失和8q的增加与患者预后不良有关。这项建议的总体目标是建立和鉴定成年前列腺中有条件地丢失Nkx3.1和获得Myc的小鼠。我们假设Nkx3.1的缺失和Myc的获得之间的协同作用将导致PIN病变进展为浸润性癌和最终的转移性疾病。本研究的具体目标如下：1)建立和鉴定Cre介导的前列腺内重组过表达Myc的转基因小鼠。2)建立并鉴定Nkx3.1基因缺失和Myc基因在前列腺中高表达的小鼠模型。3)在这些模型中检测前列腺癌发生过程中发生改变的遗传途径，特别是已知的在人类前列腺癌中常见的改变途径。这项提议寻求开发前列腺癌的体内遗传模型，以重现人类疾病。这将为研究导致前列腺癌的分子事件提供重要工具。

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.