A wide panel of microtubule-associated proteins and kinases is involved in coordinated regulation of the microtubule cytoskeleton and may thus represent valuable molecular markers contributing to major cellular pathways deregulated in cancer. We previously identified a panel of 17 microtubule-related (MT-Rel) genes that are differentially expressed in breast tumors showing resistance to taxane-based chemotherapy. In the present study, we evaluated the expression, prognostic value and functional impact of these genes in breast cancer. We show that 14 MT-Rel genes (KIF4A,ASPM,KIF20A,KIF14,TPX2,KIF18B,KIFC1,AURKB,KIF2C,GTSE1,KIF15,KIF11,RACGAP1,STMN1) are up-regulated in breast tumors compared with adjacent normal tissue. Six of them (KIF4A,ASPM,KIF20A,KIF14,TPX2,KIF18B) are overexpressed by more than 10-fold in tumor samples and four of them (KIF11,AURKB,TPX2andKIFC1) are essential for cell survival. Overexpression of all 14 genes, and underexpression of 3 other MT-Rel genes (MAST4,MAPTandMTUS1) are associated with poor breast cancer patient survival. A Systems Biology approach highlighted three major functional networks connecting the 17 MT-Rel genes and their partners, which are centered on spindle assembly, chromosome segregation and cytokinesis. Our studies identified mitotic Aurora kinases and their substrates as major targets for therapeutic approaches against breast cancer.
大量微管相关蛋白及激酶参与微管细胞骨架的协同调控，这些分子可能成为癌症中关键细胞通路失调的重要分子标志物。我们先前鉴定出17个在紫杉烷类化疗耐药性乳腺癌组织中差异表达的微管相关基因。本研究评估了这些基因在乳腺癌中的表达特征、预后价值及功能影响。结果显示，与癌旁正常组织相比，14个微管相关基因在肿瘤组织中表达上调，其中6个基因在肿瘤样本中表达上调超过10倍，4个基因对细胞存活至关重要。这14个基因的过表达及另外3个微管相关基因的低表达均与乳腺癌患者不良预后相关。系统生物学分析揭示了连接这17个微管相关基因及其相互作用因子的三大功能网络，主要聚焦于纺锤体组装、染色体分离和胞质分裂过程。我们的研究证实有丝分裂极光激酶及其底物可作为乳腺癌治疗的重要靶点。
A Network of 17 Microtubule-Related Genes Highlights Functional Deregulations in Breast Cancer
肿瘤(癌症)患者之家