Exploiting DNA repair defects in triple negative breast cancer to improve cell killing.
Exploiting DNA repair defects in triple negative breast cancer to improve cell killing.
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DOI：
10.1177/1758835920958354
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发表时间：
2020
影响因子：
4.9
通讯作者：
Gassman NR
中科院分区：
文献类型：
--
作者：
Lee KJ;Mann E;Wright G;Piett CG;Nagel ZD;Gassman NR
缺乏三阴性乳腺癌（TNBC）的分子靶点限制了治疗选择并降低了生存率。确定新的分子靶点可能有助于提高患者生存率，减少复发和转移。由于DNA修复缺陷在乳腺癌中普遍存在，我们评估了临床前模型中DNA修复蛋白的表达和修复能力。使用荧光多重宿主细胞再活化（FM-HCR）测定法，在四种TNBC细胞系MDA-MB-157（MDA-157）、MDA-MB-231（MDA-231）、MDA-MB-468（MDA-468）和HCC 1806中分析DNA修复能力。用RNA-seq分析DNA修复基因的表达，并用免疫印迹评估蛋白质表达。在细胞系中评价了对DNA损伤反应抑制剂和主要化疗药物多柔比星或卡铂的组合的反应。在临床前TNBC模型中观察到碱基切除和核苷酸切除修复的缺陷。基因表达分析表明，这些缺陷之间的相关性有限。蛋白质表达的缺失是这些DNA修复缺陷的更好指标。在TNBC临床前模型中观察到PARP 1、XRCC 1、RPA、DDB 1和ERCC 1的过表达，并且可能导致对化疗和DNA损伤反应（DDR）抑制剂的敏感性改变。当主要治疗与ATM、ATR或CHK 1的DDR抑制剂组合时，实现了改善的细胞杀伤。碱基切除和核苷酸切除修复途径可能为TNBC提供新的分子靶点。在评估新疗法时应考虑DNA修复途径的功能状态，并可能改善DDR抑制剂的主要和联合疗法的靶向。
The lack of molecular targets for triple negative breast cancer (TNBC) has limited treatment options and reduced survivorship. Identifying new molecular targets may help improve patient survival and decrease recurrence and metastasis. As DNA repair defects are prevalent in breast cancer, we evaluated the expression and repair capacities of DNA repair proteins in preclinical models. DNA repair capacity was analyzed in four TNBC cell lines, MDA-MB-157 (MDA-157), MDA-MB-231 (MDA-231), MDA-MB-468 (MDA-468), and HCC1806, using fluorescence multiplex host cell reactivation (FM-HCR) assays. Expression of DNA repair genes was analyzed with RNA-seq, and protein expression was evaluated with immunoblot. Responses to the combination of DNA damage response inhibitors and primary chemotherapy drugs doxorubicin or carboplatin were evaluated in the cell lines. Defects in base excision and nucleotide excision repair were observed in preclinical TNBC models. Gene expression analysis showed a limited correlation between these defects. Loss in protein expression was a better indicator of these DNA repair defects. Over-expression of PARP1, XRCC1, RPA, DDB1, and ERCC1 was observed in TNBC preclinical models, and likely contributed to altered sensitivity to chemotherapy and DNA damage response (DDR) inhibitors. Improved cell killing was achieved when primary therapy was combined with DDR inhibitors for ATM, ATR, or CHK1. Base excision and nucleotide excision repair pathways may offer new molecular targets for TNBC. The functional status of DNA repair pathways should be considered when evaluating new therapies and may improve the targeting for primary and combination therapies with DDR inhibitors.
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影响因子：
3.1
作者：
Akashi-Tanaka, Sadako;Watanabe, Chie;Nakamura, Seigo
通讯作者：
Nakamura, Seigo
影响因子：
16.6
作者：
Cortes-Ciriano I;Lee S;Park WY;Kim TM;Park PJ
通讯作者：
Park PJ
DOI：
10.1038/nrm.2017.53
发表时间：
2017-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Ray Chaudhuri A;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
11.2
作者：
Belanger, Francois;Fortier, Emile;Drobetsky, Elliot
通讯作者：
Drobetsky, Elliot
影响因子：
6.4
作者：
Britten, RA;Liu, D;Murray, D
通讯作者：
Murray, D