Synergistic chemosensitivity of triple-negative breast cancer cell lines to poly(ADP-Ribose) polymerase inhibition, gemcitabine, and cisplatin.
Synergistic chemosensitivity of triple-negative breast cancer cell lines to poly(ADP-Ribose) polymerase inhibition, gemcitabine, and cisplatin.
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DOI：
10.1158/0008-5472.can-09-4521
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发表时间：
2010-10-15
期刊：
影响因子：
11.2
通讯作者：
Ford JM
中科院分区：
文献类型：
--
作者：
Hastak K;Alli E;Ford JM
乳腺癌的基底样亚型的特征在于“三阴性”（TN）表型（ER-、PR-、HER 2/neu-）。TN乳腺癌与BRCA 1相关乳腺癌有相似的基因表达谱和DNA修复缺陷。BRCA 1突变细胞对吉西他滨、顺铂和PARP抑制剂表现出敏感性，因此，我们假设TN癌细胞也可能对这些药物表现出敏感性。在这项研究中，我们报告说，与非TN乳腺癌细胞相比，TN乳腺癌细胞对这些药物更敏感。此外，联合治疗表明，通过小分子抑制剂PJ 34或siRNA敲低的PARP抑制与吉西他滨和顺铂在TN细胞中协同作用，但在管腔癌细胞中不协同作用。TN细胞在PARP抑制后表现出UV诱导的环丁烷嘧啶二聚体的修复减少，表明PJ 34和吉西他滨或顺铂的协同作用反映了无效的核苷酸切除修复。机制研究表明，在TN细胞中，PJ 34降低了Δ Np 63 α的水平，同时增加了p73及其下游靶点p21的水平。因此，对联合治疗的敏感性似乎是由持续的DNA损伤和低效的DNA修复引发p63/p73介导的细胞凋亡介导的。我们的研究结果提出了一种新的治疗策略来治疗女性TN乳腺癌，一种侵袭性疾病，目前缺乏有效的治疗方案。
The basal-like subtype of breast cancer is characterized by a “triple negative” (TN) phenotype (ER-, PR-, HER2/neu-). TN breast cancers share similar gene expression profiles and DNA repair deficiencies with BRCA1-associated breast cancers. BRCA1 mutant cells exhibit sensitivity to gemcitabine, cisplatin and PARP inhibition, therefore, we hypothesized that TN cancer cells may also exhibit sensitivity to these drugs. In this study, we report that TN breast cancer cells are more sensitive to these drugs compared to non-TN breast cancer cells. Moreover, combination treatments indicated that PARP inhibition by the small molecule inhibitor PJ34 or siRNA knockdown synergized with gemcitabine and cisplatin in TN cells but not in luminal cancer cells. TN cells exhibited reduced repair of UV-induced cyclobutane pyrimidine dimers after PARP inhibition, suggesting that the synergistic effect of PJ34 and gemcitabine or cisplatin reflected inefficient nucleotide excision repair. Mechanistic investigations revealed that in TN cells PJ34 reduced levels of ΔNp63α with a concurrent increase in p73 and its downstream target p21. Thus, the sensitivity to combination treatment appeared to be mediated by sustained DNA damage and inefficient DNA repair triggering p63/p73-mediated apoptosis. Our results suggest a novel therapeutic strategy to treat women with TN breast cancer, an aggressive disease which presently lacks effective treatment options.