BRCA1 RING Function Is Essential for Tumor Suppression but Dispensable for Therapy Resistance

被引：211

作者：

Drost, Rinske ^{[1
,2
]}

Bouwman, Peter ^{[1
,2
]}

Rottenberg, Sven ^{[1
,2
]}

Boon, Ute ^{[1
,2
]}

Schut, Eva ^{[1
,2
]}

Klarenbeek, Sjoerd ^{[1
,2
]}

Klijn, Christiaan ^{[1
,2
]}

van der Heijden, Ingrid ^{[1
,2
]}

van der Gulden, Hanneke ^{[1
,2
]}

Wientjens, Ellen ^{[1
,2
]}

Pieterse, Mark ^{[1
,2
]}

Catteau, Aurelie ^{[3
]}

Green, Pete ^{[3
]}

Solomon, Ellen ^{[3
]}

Morris, Joanna R. ^{[3
]}

Jonkers, Jos ^{[1
,2
]}

机构：

[1] Netherlands Canc Inst, Div Mol Biol, NL-1066 CX Amsterdam, Netherlands

[2] Netherlands Canc Inst, Canc Syst Biol Ctr, NL-1066 CX Amsterdam, Netherlands

[3] Kings Coll London, Dept Med & Mol Genet, London SE1 9RT, England

来源：

CANCER CELL | 2011年 / 20卷 / 06期

关键词：

CANCER-PREDISPOSING MUTATIONS; DIRECTED DNA-REPAIR; E3 LIGASE ACTIVITY; BREAST-CANCER; MAMMARY-TUMORS; MOUSE MODELS; POLY(ADP-RIBOSE) POLYMERASE; NEOADJUVANT CHEMOTHERAPY; BRCA2-DEFICIENT TUMORS; CISPLATIN RESISTANCE;

D O I：

10.1016/j.ccr.2011.11.014

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Hereditary breast cancers are frequently caused by germline BRCA1 mutations. The BRCA1(C61G) mutation in the BRCA1 RING domain is a common pathogenic missense variant, which reduces BRCA1/BARD1 heterodimerization and abrogates its ubiquitin ligase activity. To investigate the role of BRCA1 RING function in tumor suppression and therapy response, we introduced the Brca1(C61G) mutation in a conditional mouse model for BRCA1 -associated breast cancer. In contrast to BRCA1 -deficient mammary carcinomas, tumors carrying the Brca1(C61G) mutation responded poorly to platinum drugs and PARP inhibition and rapidly developed resistance while retaining the Brca1(C61G) mutation. These findings point to hypomorphic activity of the BRCA1-C61G protein that, although unable to prevent tumor development, affects response to therapy.

引用

收藏

页码：797 / 809

页数：13

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