Modeling Prostate Cancer by Conditional Gene Targeting

通过条件基因靶向模拟前列腺癌

• 批准号: 6761003
• 负责人: Sarki A. Abdulkadir
• 金额: $ 22.58万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6761003
• 关键词: androgens; angiogenesis; apoptosis; carcinogenesis; cell cycle; cell cycle proteins; cell proliferation; chromosome aberrations; disease /disorder model; enzyme inhibitors; gene expression; gene mutation; gene targeting; genetic models; genetically modified animals; immunocytochemistry; laboratory mouse; male castration; metastasis; model design /development; neoplasm /cancer genetics; oncogenes; polymerase chain reaction; prostate neoplasms; prostate specific antigen; protein kinase; protooncogene

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.

目前大多数前列腺癌转基因小鼠模型都存在一个缺点，即起始癌基因（SV40 T 抗原）在人类疾病的发病机制中没有已知的作用。 因此，基于人类前列腺癌中常见的遗传病变产生改进的前列腺癌小鼠模型至关重要。 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 号染色体短臂的序列丢失和长臂的序列增加。 位于 8p21 的肿瘤抑制因子的有力候选者是 Nkx3.1，这是一种含有同源盒的蛋白质，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。 这些小鼠出现侵袭前 PIN 病变。 Myc 癌基因定位于 8q24，是许多前列腺肿瘤中扩增的靶标。 Myc 的过度表达在 PIN 病变、原发癌和转移瘤中逐渐增加，表明 Myc 过度表达与肿瘤进展相关。有趣的是，在前列腺癌中，8q24 的增加常常伴随着 8p21 的丢失，并且同时发生 8p 丢失和 8q 增加与患者预后不良相关。该提案的总体目标是生成并表征在成年前列腺中有条件丧失 Nkx3.1 并获得 Myc 的小鼠。 我们假设 Nkx3.1 的缺失和 Myc 的增加之间的协同作用将导致 PIN 病变进展为浸润性癌并最终发展为转移性疾病。 提出以下具体目标： 1) 产生并表征在前列腺中 Cre 介导的重组后过度表达 Myc 的转基因小鼠。 2) 生成并表征前列腺中同时缺失 Nkx3.1 和 Myc 过度表达的小鼠。 3）检查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能够概括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。