Genotoxic stress leads to centrosome amplification in breast cancer cell lines that have an inactive G1/S cell cycle checkpoint
Genotoxic stress leads to centrosome amplification in breast cancer cell lines that have an inactive G1/S cell cycle checkpoint
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DOI：
10.1038/sj.onc.1207568
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发表时间：
2004-05-20
期刊：
影响因子：
8
通讯作者：
Salisbury, JL
中科院分区：
文献类型：
--
作者：
D'Assoro, AB;Busby, R;Salisbury, JL
中心体扩增在癌症发生和发展过程中染色体不稳定性的起源中起着关键作用。本研究利用具有不同p53背景的乳腺癌细胞系，研究基因毒性应激、G(1)/S细胞周期检查点完整性与中心体扩增发展之间的关系。羟基脲（HU）或柔红霉素（DR）在MCF-7细胞系中引入DNA损伤，导致G(1)/S细胞周期进程和中心粒复制停止。在这些携带功能性p53的细胞中，HU处理还导致p53和p21（WAF1）的核积累，视网膜母细胞瘤低磷酸化和细胞周期蛋白a的下调。携带重组显性阴性p53突变体（vMCF-7(DNp53)）的MCF-7细胞表现出细胞周期G(1)期缩短，并保持正常的中心体表型。然而，这些细胞在HU处理后出现了扩增的中心体。MDA-MB 231细胞系在两个等位基因上都携带突变p53，在开始时显示出扩增的中心体，并在HU处理后发展为超扩增的中心体表型。在携带有缺陷p53的细胞中，中心体扩增的发展也发生在另一种DNA损伤剂dr的治疗后。综上所述，这些发现表明，p53功能的丧失本身并不足以驱动中心体扩增，但在通过取消G(1)/S细胞周期检查点导致DNA损伤后的这一过程中起着关键作用。此外，这些研究具有重要的临床意义，因为它们表明p53功能受损的乳腺癌在接受基因毒性抗癌药物治疗后可能出现中心体扩增和随之而来的染色体不稳定。
Centrosome amplification plays a key role in the origin of chromosomal instability during cancer development and progression. In this study, breast cancer cell lines with different p53 backgrounds were used to investigate the relationship between genotoxic stress, G(1)/S cell cycle checkpoint integrity, and the development of centrosome amplification. Introduction of DNA damage in the MCF-7 cell line by treatment with hydroxyurea (HU) or daunorubicin (DR) resulted in the arrest of both G(1)/S cell cycle progression and centriole duplication. In these cells, which carry functional p53, HU treatment also led to nuclear accumulation of p53 and p21(WAF1), retinoblastoma hypophosphorylation, and downregulation of cyclin A. MCF-7 cells carrying a recombinant dominant-negative p53 mutant (vMCF-7(DNp53)) exhibited a shortened G(1) phase of the cell cycle and retained a normal centrosome phenotype. However, these cells developed amplified centrosomes following HU treatment. The MDA-MB 231 cell line, which carries mutant p53 at both alleles, showed amplified centrosomes at the outset, and developed a hyperamplified centrosome phenotype following HU treatment. In cells carrying defective p53, the development of centrosome amplification also occurred following treatment with another DNA damaging agent, DR. Taken together, these findings demonstrate that loss of p53 function alone is not sufficient to drive centrosome amplification, but plays a critical role in this process following DNA damage through abrogation of the G(1)/S cell cycle checkpoint. Furthermore, these studies have important clinical implications because they suggest that breast cancers with compromised p53 function may develop centrosome amplification and consequent chromosomal instability following treatment with genotoxic anticancer drugs.