Popken-Harris Pamela, Kirchhof Nicole, Harrison Ben, Harris Lester F
David F. Hickok Memorial Cancer Research Laboratory, Abbott Northwestern Hospital, Mpls., MN 54407, USA.
Virus Res. 2006 Aug;119(2):177-86. doi: 10.1016/j.virusres.2006.01.006. Epub 2006 Feb 15.
Exogenous infection by milk-borne mouse mammary tumor viruses (MMTV) typically induce mouse mammary tumors in genetically susceptible mice at a rate of 90-95% by 1 year of age. In contrast to other transforming retroviruses, MMTV acts as an insertional mutagen and under the influence of steroid hormones induces oncogenic transformation after insertion into the host genome. As these events correspond with increases in adjacent proto-oncogene transcription, we used expression array profiling to determine which commonly associated MMTV insertion site proto-oncogenes were transcriptionally active in MMTV induced mouse mammary tumors. To verify our gene expression array results we developed real-time quantitative RT-PCR assays for the common MMTV insertion site genes found in RIII/Sa mice (int-1/wnt-1, int-2/fgf-3, int-3/Notch 4, and fgf8/AIGF) as well as two genes that were consistently up regulated (CCND1, and MAT-8) and two genes that were consistently down regulated (FN1 and MAT-8) in the MMTV induced tumors as compared to normal mammary gland. Finally, each tumor was also examined histopathologically. Our expression array findings support a model whereby just one or a few common MMTV insertions into the host genome sets up a dominant cascade of events that leave a characteristic molecular signature.
通过乳汁传播的小鼠乳腺肿瘤病毒（MMTV）的外源性感染通常会在1岁时以90 - 95%的发生率在基因易感小鼠中诱发小鼠乳腺肿瘤。与其他转化逆转录病毒不同，MMTV作为一种插入诱变剂，在类固醇激素的影响下，插入宿主基因组后诱导致癌转化。由于这些事件与相邻原癌基因转录的增加相对应，我们使用表达阵列分析来确定哪些常见的与MMTV插入位点相关的原癌基因在MMTV诱导的小鼠乳腺肿瘤中具有转录活性。为了验证我们的基因表达阵列结果，我们针对在RIII/Sa小鼠中发现的常见MMTV插入位点基因（int-１/wnt-1、int-2/fgf-3、int-3/Notch 4和fgf8/AIGF）以及在MMTV诱导的肿瘤中与正常乳腺相比持续上调的两个基因（CCND1和MAT-8）和持续下调的两个基因（FN1和MAT-8）开发了实时定量RT-PCR检测方法。最后，对每个肿瘤进行了组织病理学检查。我们的表达阵列研究结果支持这样一种模型，即MMTV在宿主基因组中的一两个常见插入会引发一系列占主导地位的事件，留下特征性的分子印记。
