Chromosomal instability and lack of cyclin E regulation in hCdc4 mutant human breast cancer cells.
Chromosomal instability and lack of cyclin E regulation in hCdc4 mutant human breast cancer cells.
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DOI：
10.1186/bcr900
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Ethier SP
中科院分区：
文献类型：
--
作者：
Willmarth NE;Albertson DG;Ethier SP
细胞周期蛋白E是G1期细胞周期蛋白，对G1-S期转变至关重要，已知其对肿瘤发生具有深远影响。细胞周期蛋白E水平的升高与乳腺癌有关，在乳腺癌中观察到的染色体不稳定性被认为与细胞周期蛋白E的组成性表达有关。以前的研究表明，SUM 149 PT人乳腺癌细胞通过Western分析显示出非常高水平的细胞周期蛋白E表达，并且由于F-box蛋白hCdc 4中的突变，它们表达非功能性细胞周期蛋白E泛素连接酶。我们使用Western印迹分析和流式细胞术检测了MCF 10A和SUM 149 PT细胞中细胞周期蛋白E的表达。免疫荧光法用于定位细胞周期蛋白E在正常和乳腺癌细胞。此外，进行阵列比较基因组杂交分析，以比较一组乳腺癌细胞系中染色体拷贝数改变与细胞周期蛋白E表达水平。SUM 149 PT细胞在细胞周期的持续时间内以每个细胞为基础过表达细胞周期蛋白E。高水平的细胞周期蛋白E维持整个S期，和SUM 149 PT细胞表现出S期延迟或逮捕可能是由于细胞周期蛋白E过表达。此外，比较基因组杂交表明，SUM 149 PT细胞表现出许多染色体拷贝数的改变，这可能反映了先前或正在进行的基因组不稳定性。然而，在一组人乳腺癌细胞系中，没有观察到细胞周期蛋白E水平和基因组拷贝数改变之间的直接相关性。细胞周期蛋白E在SUM 149 PT细胞的整个细胞周期中以高水平过表达，这与在正常细胞的S期中期至晚期观察到的细胞周期蛋白E降解形成鲜明对比。SUM 149 PT细胞不能调节细胞周期蛋白E，也表现出许多拷贝数的改变。然而，在一组其他乳腺癌细胞系中，细胞周期蛋白E过表达和染色体不稳定性之间缺乏直接相关性。
Cyclin E, a G1 cyclin essential for G1–S phase transition, is known to have a profound effect on tumorigenesis. Elevated levels of cyclin E have been associated with breast cancer, and chromosomal instability observed in breast cancer is suggested to be associated with constitutive expression of cyclin E. It was previously demonstrated that SUM149PT human breast cancer cells show very high levels of cyclin E expression by western analysis and that they express a nonfunctional cyclin E ubiquitin ligase due to a mutation in the F-box protein hCdc4. We examined cyclin E expression in both MCF10A and SUM149PT cells using western blot analysis and flow cytometry. Immunofluorescence was utilized for the localization of cyclin E in both normal and breast cancer cells. In addition, array comparative genomic hybridization analysis was performed to compare chromosome copy number alterations with levels of cyclin E expression among a panel of breast cancer cell lines. SUM149PT cells overexpress cyclin E on a cell per cell basis for the duration of the cell cycle. High cyclin E levels are maintained throughout the S phase, and SUM149PT cells exhibit an S phase delay or arrest probably due to cyclin E overexpression. In addition, comparative genomic hybridization indicated that SUM149PT cells exhibit many chromosome copy number alterations, which may reflect prior or ongoing genomic instability. However, no direct correlation was observed between cyclin E levels and genomic copy number alteration in a panel of human breast cancer cell lines. Cyclin E is overexpressed at high levels throughout the cell cycle in SUM149PT cells, which is in stark contrast to cyclin E degradation observed in the mid to late S phase of normal cells. SUM149PT cells are unable to regulate cyclin E and also exhibit many copy number alterations. However, there was a lack of direct correlation between cyclin E overexpression and chromosomal instability across a panel of other breast cancer cell lines examined.
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