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起始癌基因（SV 40 T抗原）在人类疾病的发病机制中没有已知的作用。 因此，关键是要产生一种改进的前列腺癌小鼠模型，该模型基于在人前列腺癌中通常观察到的遗传病变。 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号染色体短臂序列的丢失和长臂序列的获得。位于8 p21的肿瘤抑制因子的强有力候选者是Nkx3.1，一种含有同源框的蛋白质，其表达在许多前列腺肿瘤和前列腺上皮内瘤变（PIN）病变中丢失。 我们已经使用Cre/loxP介导的重组产生成年前列腺中Nkx3.1缺失的小鼠。 这些小鼠发生了侵入前PIN病变。 Myc癌基因定位于8 q24，是许多前列腺肿瘤扩增的靶点。在PIN病变、原发癌和转移瘤中，Myc的过度表达逐渐增加，表明Myc过度表达与肿瘤进展相关。有趣的是，在前列腺癌中，8 q24的增加通常伴随着8 p21的丢失，同时8 p的丢失和8 q的增加与患者预后不良相关。该提案的总体目标是产生和表征成年前列腺中Nkx3.1有条件丧失和Myc获得的小鼠。 我们推测Nkx3.1的丢失和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。 提出了以下具体目的：1）产生和表征在前列腺中Cre介导的重组后过表达Myc的转基因小鼠。 2)产生并表征前列腺中同时缺失Nkx3.1和过表达Myc的小鼠。 3)研究这些模型中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通常改变的途径。 该提案旨在开发一种重现人类疾病的前列腺癌体内遗传模型。 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.