A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair.
A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair.
复制标题
BRCA1卷曲-卷曲结构域变体破坏PALB2相互作用促进乳腺肿瘤的发展，并在同源重组修复中赋予可定位的缺陷。
DOI：
10.1158/0008-5472.can-21-1415
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发表时间：
2021-12-15
期刊：
影响因子：
11.2
通讯作者：
Jonkers J
中科院分区：
文献类型：
--
作者：
Pulver EM;Mukherjee C;van de Kamp G;Roobol SJ;Rother MB;van der Gulden H;de Bruijn R;Lattanzio MV;van der Burg E;Drenth AP;Verkaik NS;Hahn K;Klarenbeek S;de Korte-Grimmerink R;van de Ven M;Pritchard CEJ;Huijbers IJ;Xia B;van Gent DC;Essers J;van Attikum H;Ray Chaudhuri A;Bouwman P;Jonkers J
The BRCA1 tumor suppressor gene encodes a multi-domain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks (DSB), which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered variants of uncertain clinical significance (VUS). Using genetically engineered mice, we show here that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupts the interaction with PALB2 and leads to embryonic lethality. Brca1 p.L1363P led to a similar acceleration in the development of Trp53-deficient mammary tumors as Brca1 loss, but the tumors showed distinct histopathological features, with more stable DNA copy number profiles in Brca1 p.L1363P tumors. Nevertheless, Brca1 p.L1363P mammary tumors were HRR-incompetent and responsive to cisplatin and PARP inhibition. Overall, these results provide the first direct evidence that a BRCA1 missense variant outside of the RING and BRCT domains increases the risk of breast cancer.
