Defective repair of oxidative dna damage in triple-negative breast cancer confers sensitivity to inhibition of poly(ADP-ribose) polymerase.
Defective repair of oxidative dna damage in triple-negative breast cancer confers sensitivity to inhibition of poly(ADP-ribose) polymerase.
复制标题
三阴性乳腺癌中氧化DNA损伤的修复缺陷导致对聚(ADP-核糖)聚合酶的抑制敏感。
DOI：
10.1158/0008-5472.can-08-4016
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发表时间：
2009-04-15
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：
Alli E;Sharma VB;Sunderesakumar P;Ford JM
代表乳房中两种主要类型上皮细胞（管腔型和基底型）的乳腺癌亚型具有不同的组织病理学特征。基底细胞样亚型乳腺癌，包括大多数由于乳腺癌易感基因1（BRCA 1）突变引起的遗传性乳腺癌，通常呈现三阴性状态，即缺乏雌激素受体-α和孕酮受体的表达，缺乏HER 2/NEU癌基因的过表达或扩增。DNA损伤反应途径中的缺陷导致基因组不稳定并导致致癌，但也可用于治疗目的。我们通过碱基切除修复（BER）途径分析了氧化性DNA损伤（ODD）的修复，该途径异常时会导致基因组不稳定和乳腺癌发生，在代表乳腺癌不同亚型的细胞系中，并存在BRCA 1缺陷。我们发现基底样和BRCA 1突变的乳腺癌细胞在ODD的BER中存在缺陷，并且这种缺陷赋予了对DNA修复酶聚（ADP-核糖）聚合酶抑制的敏感性。该缺陷可能至少部分归因于BRCA 1在BER途径中的新作用。总的来说，这些数据提供了预防，预后和治疗的有用性。
Subtypes of breast cancer that represent the two major types of epithelial cells in the breast (luminal and basal) carry distinct histopathological profiles. Breast cancers of the basal-like subtype, which include the majority of hereditary breast cancers due to mutations in the Breast Cancer Susceptibility Gene 1 (BRCA1), frequently assume triple-negative status, i.e. they lack expression of estrogen receptor-α and progesterone receptor and lack overexpression or amplification of the HER2/NEU oncogene. Defects in DNA damage response pathways result in genome instability and lead to carcinogenesis, but may also be exploited for therapeutic purposes. We analyzed repair of oxidative DNA damage (ODD) by the base-excision repair (BER) pathway, which when aberrant leads to genomic instability and breast carcinogenesis, in cell lines that represent the different subtypes of breast cancer and in the presence of BRCA1 deficiency. We found that basal-like and BRCA1-mutated breast cancer cells were defective in BER of ODD, and that this defect conferred sensitivity to inhibition of poly(ADP-ribose) polymerase, a DNA repair enzyme. The defect may be attributed, at least in part, to a novel role for BRCA1 in the BER pathway. Overall, these data offer preventive, prognostic, and therapeutic usefulness.