基因组共扩增上调有丝分裂基因网络活性，该活性可预测乳腺癌的预后及对有丝分裂蛋白抑制剂的反应。
Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer.
作者信息
Hu Zhi, Mao Jian-Hua, Curtis Christina, Huang Ge, Gu Shenda, Heiser Laura, Lenburg Marc E, Korkola James E, Bayani Nora, Samarajiwa Shamith, Seoane Jose A, Dane Mark A, Esch Amanda, Feiler Heidi S, Wang Nicholas J, Hardwicke Mary Ann, Laquerre Sylvie, Jackson Jeff, W Wood Kenneth, Weber Barbara, Spellman Paul T, Aparicio Samuel, Wooster Richard, Caldas Carlos, Gray Joe W
机构信息
Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, 3303 SW Bond Ave., CH13B, Portland, OR, 97239, USA.
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94127, USA.
出版信息
Breast Cancer Res. 2016 Jul 1;18(1):70. doi: 10.1186/s13058-016-0728-y.
BACKGROUND
High mitotic activity is associated with the genesis and progression of many cancers. Small molecule inhibitors of mitotic apparatus proteins are now being developed and evaluated clinically as anticancer agents. With clinical trials of several of these experimental compounds underway, it is important to understand the molecular mechanisms that determine high mitotic activity, identify tumor subtypes that carry molecular aberrations that confer high mitotic activity, and to develop molecular markers that distinguish which tumors will be most responsive to mitotic apparatus inhibitors.
METHODS
We identified a coordinately regulated mitotic apparatus network by analyzing gene expression profiles for 53 malignant and non-malignant human breast cancer cell lines and two separate primary breast tumor datasets. We defined the mitotic network activity index (MNAI) as the sum of the transcriptional levels of the 54 coordinately regulated mitotic apparatus genes. The effect of those genes on cell growth was evaluated by small interfering RNA (siRNA).
RESULTS
High MNAI was enriched in basal-like breast tumors and was associated with reduced survival duration and preferential sensitivity to inhibitors of the mitotic apparatus proteins, polo-like kinase, centromere associated protein E and aurora kinase designated GSK462364, GSK923295 and GSK1070916, respectively. Co-amplification of regions of chromosomes 8q24, 10p15-p12, 12p13, and 17q24-q25 was associated with the transcriptional upregulation of this network of 54 mitotic apparatus genes, and we identify transcription factors that localize to these regions and putatively regulate mitotic activity. Knockdown of the mitotic network by siRNA identified 22 genes that might be considered as additional therapeutic targets for this clinically relevant patient subgroup.
CONCLUSIONS
We define a molecular signature which may guide therapeutic approaches for tumors with high mitotic network activity.
背景
高有丝分裂活性与多种癌症的发生和进展相关。有丝分裂装置蛋白的小分子抑制剂目前正在作为抗癌药物进行临床开发和评估。随着其中几种实验性化合物的临床试验正在进行，了解决定高有丝分裂活性的分子机制、识别携带赋予高有丝分裂活性分子畸变的肿瘤亚型以及开发区分哪些肿瘤对有丝分裂装置抑制剂最敏感的分子标志物非常重要。
方法
我们通过分析53个人类恶性和非恶性乳腺癌细胞系以及两个独立的原发性乳腺肿瘤数据集的基因表达谱，确定了一个协同调节的有丝分裂装置网络。我们将有丝分裂网络活性指数（MNAI）定义为54个协同调节的有丝分裂装置基因转录水平的总和。通过小干扰RNA（siRNA）评估这些基因对细胞生长的影响。
结果
高MNAI在基底样乳腺肿瘤中富集，与生存时间缩短以及对有丝分裂装置蛋白抑制剂（分别为polo样激酶、着丝粒相关蛋白E和极光激酶，命名为GSK462364、GSK923295和GSK1070916）的优先敏感性相关。染色体8q24、10p15 - p12、12p13和17q24 - q25区域的共扩增与这54个有丝分裂装置基因网络的转录上调相关，并且我们鉴定了定位于这些区域并可能调节有丝分裂活性的转录因子。通过siRNA敲低有丝分裂网络确定了22个基因，这些基因可能被视为该临床相关患者亚组的额外治疗靶点。
结论
我们定义了一种分子特征，可指导对有高有丝分裂网络活性肿瘤的治疗方法。
Zotero 插件