Network modeling links breast cancer susceptibility and centrosome dysfunction
Network modeling links breast cancer susceptibility and centrosome dysfunction
复制标题
网络建模将乳腺癌易感性与中心体功能障碍联系起来
DOI：
10.1038/ng.2007.2
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发表时间：
2007-11-01
期刊：
影响因子：
30.8
通讯作者：
Vidal, Marc
中科院分区：
文献类型：
--
作者：
Pujana, Miguel Angel;Han, Jing-Dong J.;Vidal, Marc
许多癌症相关基因仍有待鉴定，以阐明癌症易感性和进展的潜在分子机制。还需要更好地了解癌症基因突变如何在复杂的细胞网络背景下影响其产物。在这里，我们使用网络建模策略来识别与乳腺癌高风险潜在相关的基因。从四个已知的编码乳腺癌肿瘤抑制因子的基因开始，我们将基因表达谱与来自不同物种的功能基因组学和蛋白质组学（或“组学”）数据相结合，生成一个包含118个基因的网络，这些基因由866个潜在的功能关联连接。这个网络显示出比预期更高的连通性，这表明它的组成部分在生物相关的通路中发挥作用。该网络的组成部分之一是HMMR，编码一个中心体亚基，我们证明了以前未知的功能与乳腺癌相关基因BRCA1。两项乳腺癌病例对照研究表明，HMMR基因座与人类乳腺癌的高风险相关。我们的网络建模策略对于发现其他癌症相关基因应该是有用的。
Many cancer-associated genes remain to be identified to clarify the underlying molecular mechanisms of cancer susceptibility and progression. Better understanding is also required of how mutations in cancer genes affect their products in the context of complex cellular networks. Here we have used a network modeling strategy to identify genes potentially associated with higher risk of breast cancer. Starting with four known genes encoding tumor suppressors of breast cancer, we combined gene expression profiling with functional genomic and proteomic ( or `omic') data from various species to generate a network containing 118 genes linked by 866 potential functional associations. This network shows higher connectivity than expected by chance, suggesting that its components function in biologically related pathways. One of the components of the network is HMMR, encoding a centrosome subunit, for which we demonstrate previously unknown functional associations with the breast cancer associated gene BRCA1. Two case-control studies of incident breast cancer indicate that the HMMR locus is associated with higher risk of breast cancer in humans. Our network modeling strategy should be useful for the discovery of additional cancer-associated genes.