Patterns of cell cycle checkpoint deregulation associated with intrinsic molecular subtypes of human breast cancer cells.
Patterns of cell cycle checkpoint deregulation associated with intrinsic molecular subtypes of human breast cancer cells.
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DOI：
10.1038/s41523-017-0009-7
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发表时间：
2017
影响因子：
5.9
通讯作者：
Kaufmann WK
中科院分区：
文献类型：
--
作者：
Bower JJ;Vance LD;Psioda M;Smith-Roe SL;Simpson DA;Ibrahim JG;Hoadley KA;Perou CM;Kaufmann WK
基因组不稳定性是乳腺癌的标志，有助于肿瘤异质性，并影响化疗耐药性。虽然Gap 2和有丝分裂检查点被认为可以防止基因组不稳定性，但这些检查点在乳腺癌中的作用知之甚少。在这里，我们评估了差距2和有丝分裂检查点功能的24个乳腺癌和永生化乳腺上皮细胞系代表四个内在的分子亚型的乳腺癌。我们发现细胞周期检查点失调的模式与乳腺癌细胞系的内在分子亚型有关。具体而言，管腔B和基底样细胞系具有两种分子上不同的Gap 2/有丝分裂检查点缺陷（分别为脱连环Gap 2检查点和纺锤体组装检查点的损伤）。检查的所有乳腺癌细胞系亚型均显示异常DNA合成/Gap 2/有丝分裂进展，基底样和封闭蛋白低细胞系显示染色单体凝聚缺陷百分比增加。此外，在细胞系组中鉴定的去连锁Gap 2检查点基因表达特征与乳腺癌患者的临床结果相关，表明乳腺肿瘤也可能存在去连锁Gap 2检查点功能缺陷。综上所述，这些数据表明，驱动这些表型的信号通路的药理学靶向可能导致后两种亚型的新型个性化治疗策略的发展，这两种亚型目前缺乏靶向治疗选择，因为它们的三阴性乳腺癌状态。乳腺癌的独特亚型显示出影响细胞分裂的基因组不稳定性的独特模式。美国查佩尔山的北卡罗来纳州大学的杰奎琳·J·鲍尔和同事们，评估了几个G2-M细胞周期检查点的分子功能，这些检查点确保细胞在DNA复制完成之前不会开始有丝分裂，并且它们有机会修复任何受损的DNA，在24个乳腺癌和乳腺上皮细胞系中，这些细胞系共同代表了乳腺癌的六种内在分子亚型中的四种。研究人员发现的细胞周期检查点失调的不同模式表明，每种类型乳腺癌中功能障碍的药理学靶向可能导致个性化治疗策略。这些发现还指出了诊断生物标志物，可以帮助预测患者对新药或现有化疗的反应。
Genomic instability is a hallmark of breast cancer, contributes to tumor heterogeneity, and influences chemotherapy resistance. Although Gap 2 and mitotic checkpoints are thought to prevent genomic instability, the role of these checkpoints in breast cancer is poorly understood. Here, we assess the Gap 2 and mitotic checkpoint functions of 24 breast cancer and immortalized mammary epithelial cell lines representing four of the six intrinsic molecular subtypes of breast cancer. We found that patterns of cell cycle checkpoint deregulation were associated with the intrinsic molecular subtype of breast cancer cell lines. Specifically, the luminal B and basal-like cell lines harbored two molecularly distinct Gap 2/mitosis checkpoint defects (impairment of the decatenation Gap 2 checkpoint and the spindle assembly checkpoint, respectively). All subtypes of breast cancer cell lines examined displayed aberrant DNA synthesis/Gap 2/mitosis progression and the basal-like and claudin-low cell lines exhibited increased percentages of chromatid cohesion defects. Furthermore, a decatenation Gap 2 checkpoint gene expression signature identified in the cell line panel correlated with clinical outcomes in breast cancer patients, suggesting that breast tumors may also harbor defects in decatenation Gap 2 checkpoint function. Taken together, these data imply that pharmacological targeting of signaling pathways driving these phenotypes may lead to the development of novel personalized treatment strategies for the latter two subtypes which currently lack targeted therapeutic options because of their triple negative breast cancer status. Unique subtypes of breast cancer display distinctive patterns of genomic instability that affect cell division. Jacquelyn J. Bower and colleagues at the University of North Carolina at Chapel Hill, USA, assessed the molecular function of several G2-M cell cycle checkpoints—which ensure that cells don’t begin mitotic cell division until DNA replication is complete and they have had a chance to repair any damaged DNA—in 24 breast cancer and mammary epithelial cell lines that collectively represent four of the six intrinsic molecular subtypes of breast cancer. The distinct patterns of cell cycle checkpoint deregulation that the researchers found suggest that pharmacological targeting of the dysfunction in each type of breast cancer could lead to personalized treatment strategies. The findings also point to diagnostic biomarkers that could help predict patient responses to novel drugs or existing chemotherapies.