miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors.
miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors.
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DOI：
10.1016/j.molcel.2010.12.005
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发表时间：
2011-01-21
期刊：
影响因子：
16
通讯作者：
Chowdhury D
中科院分区：
文献类型：
--
作者：
Moskwa P;Buffa FM;Pan Y;Panchakshari R;Gottipati P;Muschel RJ;Beech J;Kulshrestha R;Abdelmohsen K;Weinstock DM;Gorospe M;Harris AL;Helleday T;Chowdhury D
BRCA 1的表达通常在散发性乳腺肿瘤中降低，这与乳腺癌患者的预后不良相关。在这里，我们表明BRCA 1转录本选择性地富集在Argonaute/miR-182复合物中，并且miR-182下调BRCA 1表达。拮抗miR-182可提高BRCA 1蛋白水平，保护其免受IR诱导的细胞死亡，而过表达miR-182可降低BRCA 1蛋白，损害同源重组介导的修复，并使细胞对IR超敏感。与BRCA 1缺陷表型一致，miR-182过表达的乳腺肿瘤细胞对聚（ADP-核糖）聚合酶1（PARP 1）抑制剂高度敏感。相反，拮抗miR-182可提高BRCA 1水平并诱导对PARP 1抑制剂的抗性。最后，临床级PARP 1抑制剂影响动物模型中表达miR-182的肿瘤的生长。这些结果表明，miR-182介导的BRCA 1下调阻碍了DNA修复，并可能影响乳腺癌治疗。
Expression of BRCA1 is commonly decreased in sporadic breast tumors, and this correlates with poor prognosis of breast cancer patients. Here we show that BRCA1 transcripts are selectively enriched in the Argonaute/miR-182 complex and miR-182 down-regulates BRCA1 expression . Antagonizing miR-182 enhances BRCA1 protein levels and protects them from IR-induced cell death, while overexpressing miR-182 reduces BRCA1 protein, impairs homologous recombination-mediated repair, and render cells hypersensitive to IR. The impaired DNA repair phenotype induced by miR-182 overexpression can be fully rescued by over-expressing miR-182-insensitive BRCA1. Consistent with a BRCA1-deficiency phenotype, miR-182 overexpressing breast tumor cells are hypersensitive to inhibitors of poly (ADP-ribose) polymerase1 (PARP1). Conversely, antagonizing miR-182 enhances BRCA1 levels and induces resistance to PARP1 inhibitor. Finally, a clinical-grade PARP1 inhibitor impacts outgrowth of miR-182 expressing tumors in animal models. Together these results suggest that miR-182-mediated down-regulation of BRCA1 impedes DNA repair, and may impact breast cancer therapy.
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影响因子：
16
作者：
Chowdhury, Dipanjan;Xu, Xingzhi;Zhong, Xueyan;Ahmed, Fariyal;Zhong, Jianing;Liao, Ji;Dykxhoorn, Derek M.;Weinstock, David M.;Pfeifer, Gerd P.;Lieberman, Judy
通讯作者：
Lieberman, Judy
影响因子：
45.3
作者：
Atchley, Deann P.;Albarracin, Constance T.;Arun, Banu K.
通讯作者：
Arun, Banu K.
影响因子：
5.3
作者：
Baldassarre, G;Battista, S;Fusco, A
通讯作者：
Fusco, A
影响因子：
11.5
作者：
Foulkes, WD;Metcalfe, K;Narod, SA
通讯作者：
Narod, SA
影响因子：
4.5
作者：
Easow, George;Teleman, Aurelio A.;Cohen, Stephen M.
通讯作者：
Cohen, Stephen M.