The centrosomal kinase Nek2 displays elevated levels of protein expression in human breast cancer
The centrosomal kinase Nek2 displays elevated levels of protein expression in human breast cancer
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DOI：
10.1158/0008-5472.can-04-0960
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发表时间：
2004-10-15
期刊：
影响因子：
11.2
通讯作者：
Fry, AM
中科院分区：
文献类型：
--
作者：
Hayward, DG;Clarke, RB;Fry, AM
非整倍体和染色体不稳定性是人类癌症中常见的异常。有丝分裂进程失控、多极纺锤体形成和胞质分裂缺陷都可能导致这些表型。Nek2是一种细胞周期调节蛋白激酶，在有丝分裂开始时具有最大活性，定位于中心体。功能研究表明Nek2参与调节中心体分离和纺锤体形成。在这里，我们提出了人类癌细胞系和原发性肿瘤中Nek2激酶蛋白表达水平的第一项研究。Nek2蛋白在来源于一系列人类肿瘤的细胞系中升高2至5倍，所述人类肿瘤包括宫颈、卵巢、乳腺、前列腺和白血病来源的肿瘤。最重要的是，通过免疫组化，我们发现Nek2蛋白在乳腺浸润前原位导管癌和浸润性乳腺癌中显著上调。最后，异位表达的Nek2A永生化HBL100乳腺上皮细胞，我们发现，增加Nek2蛋白导致的积累多核细胞与多余的中心体。这些数据突出了Nek2激酶作为乳腺癌化疗干预的新的潜在靶点。
Aneuploidy and chromosome instability are common abnormalities in human cancer. Loss of control over mitotic progression, multipolar spindle formation, and cytokinesis defects are all likely to contribute to these phenotypes. Nek2 is a cell cycle-regulated protein kinase with maximal activity at the onset of mitosis that localizes to the centrosome. Functional studies have implicated Nek2 in regulation of centrosome separation and spindle formation. Here, we present the first study of the protein expression levels of the Nek2 kinase in human cancer cell lines and primary tumors. Nek2 protein is elevated 2- to 5-fold in cell lines derived from a range of human tumors including those of cervical, ovarian, breast, prostate, and leukemic origin. Most importantly, by immunohistochemistry, we find that Nek2 protein is significantly up-regulated in preinvasive ill situ ductal carcinomas of the breast as well as in invasive breast carcinomas. Finally, by ectopic expression of Nek2A in immortalized HBL100 breast epithelial cells, we show that increased Nek2 protein leads to accumulation of multinucleated cells with supernumerary centrosomes. These data highlight the Nek2 kinase as novel potential target for chemotherapeutic intervention in breast cancer.