Identification of novel amplification gene targets in mouse and human breast cancer at a syntenic cluster mapping to mouse ch8A1 and human ch13q34
Identification of novel amplification gene targets in mouse and human breast cancer at a syntenic cluster mapping to mouse ch8A1 and human ch13q34
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DOI：
10.1158/0008-5472.can-06-4672
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发表时间：
2007-05-01
期刊：
影响因子：
11.2
通讯作者：
Aldaz, C. Marcelo
中科院分区：
文献类型：
--
作者：
Abba, Martin C.;Fabris, Victoria T.;Aldaz, C. Marcelo
对来自可移植的p53缺失小鼠乳腺生长系的侵袭性乳腺肿瘤的一系列基因表达分析显示，Tfdp1(转录因子DP1)、LAMP1(溶酶体膜糖蛋白1)和Gas6(生长停滞特异性6)的转录本显著上调。所有这些基因都属于同一个连锁簇，定位于小鼠染色体带8a1。BAC阵列比较基因组杂交和荧光原位杂交分析显示基因组扩增位于小鼠区域ch8A1.1。最小扩增区域包含基因Cul4a、Lamp-1、Tfdp1和Gas6，在癌前阶段p53缺失的乳腺生长系及其所有来源的肿瘤中高表达。在自发性P53基因缺失的乳腺肿瘤中也观察到同样的扩增。有趣的是，这一区域与人类染色体13q34同源，其中一些相同的基因之前在人类癌症中被观察到扩增。因此，我们进一步研究了影响ch13q34基因定位的基因扩增在人类乳腺癌中的发生和频率。在所分析的74例乳腺癌中，TFDP1的扩增频率最高，达31%。CUL4A、LAMP1、TFDP1和Gas6基因的扩增在统计学上呈显著正相关(P<；0.001)。Meta分析显示，TFDP1的高表达与总生存期(P=0.00004)、无复发生存期(P=0.0119)和无转移间期(P=0.0064)显著相关。综上所述，我们的研究结果表明，CUL4A、LAMP1、TFDP1和Gas6是乳腺癌过度表达和扩增的靶点。因此，这些基因的过度表达，特别是TFDP1的过度表达，可能与人类乳腺癌的一个重要亚群的发生和/或进展有关。
Serial analysis of gene expression from aggressive mammary tumors derived from transplantable p53 null mouse mammary outgrowth lines revealed significant up-regulation of Tfdp1 (transcription factor Dp1), Lamp1 (lysosomal membrane glycoprotein 1) and Gas6 (growth arrest specific 6) transcripts. All of these genes belong to the same linkage cluster, mapping to mouse chromosome band 8A1. BAC-array comparative genomic hybridization and fluorescence in situ hybridization analyses revealed genomic amplification at mouse region ch8A1.1. The minimal region of amplification contained genes Cul4a, Lamp-1, Tfdp1, and Gas6, highly overexpressed in the p53 null mammary outgrowth lines at preneoplastic stages, and in all its derived tumors. The same amplification was also observed in spontaneous p53 null mammary tumors. Interestingly, this region is homologous to human chromosome 13q34, and some of the same genes were previously observed amplified in human carcinomas. Thus, we further investigated the occurrence and frequency of gene amplification affecting genes mapping to ch13q34 in human breast cancer. TFDP1 showed the highest frequency of amplification affecting 31% of 74 breast carcinomas analyzed. Statistically significant positive correlation was observed for the amplification of CUL4A, LAMP1, TFDP1, and GAS6 genes (P < 0.001). Meta-analysis of publicly available gene expression data sets showed a strong association between the high expression of TFDP1 and decreased overall survival (P = 0.00004), relapse-free survival (P = 0.0119), and metastasis-free interval (P = 0.0064). In conclusion, our findings suggest that CUL4A, LAMP1, TFDP1, and GAS6 are targets for overexpression and amplification in breast cancers. Therefore, overexpression of these genes and, in particular, TFDP1 might be of relevance in the development and/or progression in a significant subset of human breast carcinomas.