Modeling Prostate Tumorigenesis

项目总结 对人和小鼠前列腺癌的研究表明，含有同源结构域的转录 Nkx3.1因子是一个重要的半缺失抑癌基因，参与了前列腺癌的发生。 Nkx3.1蛋白在人和小鼠前列腺肿瘤中表达缺失，最近的一项研究发现Nkx3.1 遗传性前列腺癌的突变。我们已经产生并描述了常规的和有条件的 Nkx3.1突变小鼠。这些小鼠出现前列腺上皮增生和异型增生，并已 作为前列腺上皮内瘤变(PIN)的模型被广泛研究。在这些动物中， 前列腺腔上皮细胞从细胞周期分化延迟，导致前列腺上皮 增生和随后的PIN。对Nkx3.1突变小鼠的进一步分析揭示了几个特征 开始阐明这种蛋白质抑制肿瘤的机制。Nkx3.1规定了一类 基因的剂量敏感和随机的方式，这一现象可能是单纯性不足和 这似乎是由靶基因的不同染色质状态决定的。Nkx3.1规定了 细胞周期调节基因以及一类独特的雄激素靶基因的表达。此外，Nkx3.1的损失 调节抗氧化酶(包括过氧化还蛋白6、谷胱甘肽)的表达 过氧化物酶3和巯基氧化酶6)，导致失去对氧化损伤的保护。这是我们的 假设Nkx3.1的缺失通过解除对多个基因程序的调控来促进前列腺癌的发生 改变细胞周期退出、雄激素信号传导和抗氧化反应。我们已经概述了具体的经验- 根据以下目的来检验这一假说：1)检验 剂量敏感的Nkx3.1靶基因。2)明确雄激素诱导基因的调控和功能 特别是在Nkx3.1缺失的细胞中。3)测试抗氧化剂防御系统的破坏 Nkx3.1突变小鼠导致基因突变的积累。项目叙事 这些研究的意义在于它们有可能增加我们对这些机制的理解。 前列腺癌的启动和产生用于临床前诊断和预防的分子靶点 模特。

PROJECT SUMMARY Studies of human and mouse prostate cancer indicate that the homeodomain-containing transcription factor Nkx3.1 is an important haplo-insufficient tumor suppressor gene involved in prostate tumor initiation. Nkx3.1 protein expression is lost in human and mouse prostate tumors, and a recent study has found Nkx3.1 mutations in hereditary prostate cancer. We have generated and characterized conventional and conditional Nkx3.1 mutant mice. These mice develop prostatic epithelial hyperplasia and dysplasia and have been extensively studied as a model of prostatic intraepithelial neoplasia (PIN). In these animals, the exit of differentiating prostate luminal epithelial cells from the cell cycle is delayed, resulting in prostatic epithelial hyperplasia and subsequently PIN. Further analysis of Nkx3.1 mutant mice has revealed several features that begin to shed light on the mechanisms of tumor suppression by this protein. Nkx3.1 regulates a class of genes in a dosage-sensitive and stochastic manner, a phenomenon that may underlie haplo-insufficiency and which appears to be dictated by the differential chromatin states of target genes. Nkx3.1 regulates the expression of cell cycle regulators as well as a unique class of androgen target genes. Further, loss of Nkx3.1 dysregulates the expression of pro- and anti-oxidant enzymes (including peroxiredoxin 6, glutathione peroxidase 3 and sulfhydryl oxidase 6) resulting in loss of protection against oxidative damage. It is our hypothesis that loss of Nkx3.1 promotes prostate tumor initiation by deregulating multiple gene programs that alter cell cycle exit, androgen signaling, and the anti-oxidant response. We have outlined specific experi- ments to test this hypothesis according to the following aims: 1) To examine the regulation and function of dosage-sensitive Nkx3.1 target genes. 2) To define the regulation and function of genes induced by androgen specifically in Nkx3.1-deficient cells. 3) To test the notion that disruption of the anti-oxidant defense system in Nkx3.1 mutant mice leads to the accumulation of genetic mutations. PROJECT NARRATIVE The significance of these studies lies in their potential to increase our understanding of the mechanisms of prostate tumor initiation and to generate molecular targets for diagnosis and prevention in a preclinical model.