Abba Martín C, Hu Yuhui, Levy Carla C, Gaddis Sally, Kittrell Frances S, Hill Jamal, Bissonnette Reid P, Brown Powel H, Medina Daniel, Aldaz C Marcelo
Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
Cancer Prev Res (Phila). 2009 Feb;2(2):175-84. doi: 10.1158/1940-6207.CAPR-08-0104. Epub 2009 Jan 27.
Genetically engineered mouse cancer models are among the most useful tools for testing the in vivo effectiveness of the various chemopreventive approaches. The p53-null mouse model of mammary carcinogenesis was previously characterized by us at the cellular, molecular, and pathologic levels. In a companion article, Medina et al. analyzed the efficacy of bexarotene, gefitinib, and celecoxib as chemopreventive agents in the same model. Here we report the global gene expression effects on mammary epithelium of such compounds, analyzing the data in light of their effectiveness as chemopreventive agents. SAGE was used to profile the transcriptome of p53-null mammary epithelium obtained from mice treated with each compound versus controls. This information was also compared with SAGE data from p53-null mouse mammary tumors. Gene expression changes induced by the chemopreventive treatments revealed a common core of 87 affected genes across treatments (P < 0.05). The effective compounds, bexarotene and gefitinib, may exert their chemopreventive activity, at least in part, by affecting a set of 34 genes related to specific cellular pathways. The gene expression signature revealed various genes previously described to be associated with breast cancer, such as the activator protein-1 complex member Fos-like antigen 2 (Fosl2), early growth response 1 (Egr1), gelsolin (Gsn), and tumor protein translationally controlled 1 (Tpt1), among others. The concerted modulation of many of these transcripts before malignant transformation seems to be conducive to predominantly decrease cell proliferation. This study has revealed candidate key pathways that can be experimentally tested in the same model system and may constitute novel targets for future translational research.
基因工程小鼠癌症模型是测试各种化学预防方法体内有效性的最有用工具之一。我们之前在细胞、分子和病理水平上对乳腺致癌作用的p53基因缺失小鼠模型进行了表征。在一篇配套文章中，梅迪纳等人分析了贝沙罗汀、吉非替尼和塞来昔布在同一模型中作为化学预防剂的疗效。在此，我们报告这些化合物对乳腺上皮的整体基因表达影响，并根据它们作为化学预防剂的有效性来分析数据。使用基因表达序列分析（SAGE）来描绘从用每种化合物处理的小鼠与对照小鼠获得的p53基因缺失乳腺上皮的转录组。该信息还与来自p53基因缺失小鼠乳腺肿瘤的SAGE数据进行了比较。化学预防处理诱导的基因表达变化揭示了各处理间87个受影响基因的共同核心（P < 0.05）。有效的化合物贝沙罗汀和吉非替尼可能至少部分地通过影响一组与特定细胞途径相关的34个基因来发挥其化学预防活性。基因表达特征揭示了先前描述的与乳腺癌相关的各种基因，如激活蛋白-1复合物成员Fos样抗原2（Fosl2）、早期生长反应1（Egr1）、凝溶胶蛋白（Gsn）和翻译控制肿瘤蛋白1（Tpt1）等。在恶性转化之前对许多这些转录本的协同调节似乎主要有利于减少细胞增殖。这项研究揭示了可以在同一模型系统中进行实验测试的候选关键途径，并且可能构成未来转化研究的新靶点。
