Targeting BRCA1 localization to augment breast tumor sensitivity to poly(ADP-Ribose) polymerase inhibition.
Targeting BRCA1 localization to augment breast tumor sensitivity to poly(ADP-Ribose) polymerase inhibition.
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DOI：
10.1158/0008-5472.can-12-0934
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发表时间：
2012-11-01
期刊：
影响因子：
11.2
通讯作者：
Xia F
中科院分区：
文献类型：
--
作者：
Yang ES;Nowsheen S;Rahman MA;Cook RS;Xia F
聚（ADP-核糖）聚合酶抑制剂由于其高度选择性地杀死BRCA 1/2突变和DNA双链断裂（DSB）修复缺陷的肿瘤而获得最近的关注。不幸的是，大多数散发性乳腺癌携带野生型BRCA 1/2，并且精通DSB修复。我们和其他人已经表明，BRCA 1是一种核/细胞质穿梭蛋白，在各种刺激下从细胞核瞬时输出到胞质溶胶。因此，我们假设核BRCA 1的缺失会损害DSB修复，随后使散发性肿瘤对PARP抑制敏感。事实上，在具有功能性BRCA 1和熟练的DSB修复的人散发性乳腺癌细胞中，BRCA 1的瞬时核耗竭和随后的HR修复缺陷被截短的BRCA 1或照射诱导。这使得这些人散发性乳腺癌细胞对PARP抑制敏感。这些观察结果在遗传学上使用错误定位的BRCA 1突变体以及在体内携带乳腺肿瘤异种移植物的小鼠中得到证实。这些数据支持靶向BRCA 1位置的潜在策略，以将BRCA 1活性散发性肿瘤转化为对PARP抑制剂的合成致死组合敏感。
Poly(ADP-ribose) polymerase inhibitors have gained recent attention due to their highly selective killing of BRCA1/2 mutated and DNA double strand break (DSB) repair deficient tumors. Unfortunately, the majority of sporadic breast cancers carry wild-type BRCA1/2 and are proficient in DSB repair. We and others have shown that BRCA1 is a nuclear/cytoplasm shuttling protein which is transiently exported from the nucleus to the cytosol upon various stimuli. Thus, we hypothesized that depletion of nuclear BRCA1 would compromise DSB repair and subsequently render sporadic tumors susceptible to PARP inhibition. Indeed, in human sporadic breast cancer cells with functional BRCA1 and proficient DSB repair, a transient nuclear depletion of BRCA1 and subsequent HR repair deficit was induced with either truncated BRCA1 or irradiation. This rendered these human sporadic breast cancer cells susceptible to PARP inhibition. These observations were confirmed genetically using mislocated BRCA1 mutants as well as in vivo in mice bearing breast tumor xenografts. These data support the potential strategy of targeting BRCA1 location to convert BRCA1-proficient sporadic tumors to be susceptible to the synthetic lethal combination with PARP inhibitors.