Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer
Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer
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DOI：
10.1158/0008-5472.can-06-0486
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发表时间：
2006-08-15
期刊：
影响因子：
11.2
通讯作者：
Nikitin, Alexander Yu.
中科院分区：
文献类型：
--
作者：
Zhou, Zongxiang;Flesken-Nikitin, Andrea;Nikitin, Alexander Yu.
p53和Rb介导的通路在侵袭性人类癌症（包括前列腺癌）中经常改变。为了直接测试p53和Rb在前列腺癌发生中的作用，我们有条件地灭活了小鼠前列腺上皮中的这些基因。p53或Rb的失活导致前列腺上皮内瘤形成，由600日龄的腔上皮发展而来。相反，这两种基因的失活导致快速发展（中位生存期，226天）的癌显示管腔上皮和神经内分泌分化。由此产生的肿瘤是高度转移性的，从发展的早期阶段对雄激素耗竭具有抗性，并且标记有在人前列腺癌中常见的多个基因表达特征。有趣的是，在4 qC3和4qD2.2的增益和14 qA 2-qD 2的损失已被一致地发现通过比较基因组杂交。这些基因座分别含有Nfib、L-myc和Nkx3.1等人类癌症相关基因。我们的研究表明P53和Rb缺乏在前列腺癌发生中起关键作用，并确定了可能的继发性遗传改变。新的基因定义的模型应该是特别有价值的，为人类前列腺癌的发病机制提供新的分子见解。
Pathways mediated by p53 and Rb are frequently altered in aggressive human cancers, including prostate carcinoma. To test directly the roles of p53 and Rb in prostate carcinogenesis, we have conditionally inactivated these genes in the prostate epithelium of the mouse. Inactivation of either p53 or Rb leads to prostatic intraepithelial neoplasia developing from the luminal epithelium by 600 days of age. In contrast, inactivation of both genes results in rapidly developing (median survival, 226 days) carcinomas showing both luminal epithelial and neuroendocrine differentiation. The resulting neoplasms are highly metastatic, resistant to androgen depletion from the early stage of development, and marked with multiple gene expression signatures commonly found in human prostate carcinomas. Interestingly, gains at 4qC3 and 4qD2.2 and loss at 14qA2-qD2 have been consistently found by comparative genomic hybridization. These loci contain such human cancer-related genes as Nfib, L-myc, and Nkx3.1, respectively. Our studies show a critical role for P53 and Rb deficiency in prostate carcinogenesis and identify likely secondary genetic alterations. The new genetically defined model should be particularly valuable for providing new molecular insights into the pathogenesis of human prostate cancer.