Prostatic intraepithelial neoplasia and adenocarcinoma in mice expressing a probasin-Neu oncogenic transgene
Prostatic intraepithelial neoplasia and adenocarcinoma in mice expressing a probasin-Neu oncogenic transgene
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DOI：
10.1093/carcin/bgi324
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发表时间：
2006-05-01
期刊：
影响因子：
4.7
通讯作者：
Efstratiadis, A
中科院分区：
文献类型：
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作者：
Li, Z;Szabolcs, M;Efstratiadis, A
NEU（ERBB 2）和表皮生长因子受体（EGFR）家族的其他成员参与了人类前列腺癌（CAP）的发展和雄激素非依赖性状态的进展，但这种信号通路的参与程度和确切作用仍不清楚。为了开始在动物模型中解决这些开放性问题，我们开发了一种转基因系，其中由probasin基因启动子驱动的致癌Neu cDNA（Neu*）在小鼠前列腺中过表达，并导致前列腺上皮内瘤形成（PIN）的发展，其发展为浸润性癌。使用微阵列进行表达谱分析，通过Neu* 诱导的PIN和CAP的免疫表型选择性地验证和扩展，导致了一些新的生物标志物的鉴定，并且还揭示了Egfr、Erbb 3和磷酸化雄激素受体的表达增加。鉴于来自我们的小鼠模型的这些信息，其可用于进一步分析Erbb信号传导在前列腺肿瘤发生中的作用，我们通过免疫组织化学检查了人前列腺癌组织阵列。基于对结果的统计分析，我们提出了一个可检验的假设，即ERBB 3在我们检查的86%的人CAP病例中表达，是Erbb通路的关键元件，通过与NEU或EGFR异源二聚体化促进肿瘤发生，而NEU/EGFR二聚体似乎在CAP中没有发挥重要作用。
NEU (ERBB2) and other members of the epidermal growth factor receptor (EGFR) family have been implicated in human prostate cancer (CAP) development and progression to an androgen-independent state, but the extent of involvement and precise role of this signaling pathway remain unclear. To begin addressing such open questions in an animal model, we have developed a transgenic line in which an oncogenic Neu cDNA (Neu*) driven by the probasin gene promoter is overexpressed in the mouse prostate and causes development of prostatic intraepithelial neoplasia (PIN) that progresses to invasive carcinoma. Expression profiling using microarrays, which was selectively validated and extended by immunophenotyping of Neu*-induced PIN and CAP, led to the identification of some novel biomarkers and also revealed increased expression of Egfr, Erbb3 and phosphorylated androgen receptor. In view of this information from our mouse model, which can be used to analyze further the role of Erbb signaling in prostatic tumorigenesis, we examined human prostate cancer tissue arrays by immunohistochemistry. Based on statistical analyses of the results, we propose the testable hypothesis that ERBB3, shown to be expressed in 86% of the human CAP cases that we examined, is the pivotal element of the Erbb pathway promoting tumorigenesis by heterodimerization with NEU or EGFR, while a NEU/EGFR dimer does not appear to play a significant role in CAP.