TY - JOUR
T1 - A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair
AU - Pulver, Emilia M.
AU - Mukherjee, Chirantani
AU - van de Kamp, Gerarda
AU - Roobol, Stefan J.
AU - Rother, Magdalena B.
AU - van der Gulden, Hanneke
AU - de Bruijn, Roebi
AU - Lattanzio, Maria Valeria
AU - van der Burg, Eline
AU - Drenth, Anne Paulien
AU - Verkaik, Nicole S.
AU - Hahn, Kerstin
AU - Klarenbeek, Sjoerd
AU - de Korte-Grimmerink, Renske
AU - van de Ven, Marieke
AU - Pritchard, Colin E.J.
AU - Huijbers, Ivo J.
AU - Xia, Bing
AU - van Gent, Dik C.
AU - Essers, Jeroen
AU - van Attikum, Haico
AU - Chaudhuri, Arnab Ray
AU - Bouwman, Peter
AU - Jonkers, Jos
N1 - Funding Information:
The authors thank Jinhyuk Bhin for his assistance with bioinformatics analyses. The authors thank the NKI animal laboratory facilities and pathology unit, the NKI genomics core facility, and the NKI bioimaging facility for expert technical support. This work was supported by grants from the Dutch Cancer Society (KWF; NKI 2015-7877 to P. Bouwman, J. Jonkers, and Maaike P.G. Vreeswijk; 11008/2017-1 to A. Ray Chaudhuri; and 12092/2018 to J. Essers); the Dutch Research Council (NWO; VIDI VI. 193.131 to A. Ray Chaudhuri; VICI 91814643 to J. Jonkers; and VICI VI.C.182.052 to H. van Attikum); Oncode Institute, which is partly financed by KWF, NWO research program Mosaic (grant 017.008.022 to J. Jonkers); the Lundbeck Foundation (grant R223-2016-956 to J. Jonkers, Claus Storgaard Sørensen, and Finn Cilius Nielsen); Technologie stichting STW (project number 13577 to D.C. van Gent and J. Essers); and the Swiss National Science Foundation to K. Hahn.
Publisher Copyright:
© 2021 American Association for Cancer Research
PY - 2021/12/15
Y1 - 2021/12/15
N2 - The BRCA1 tumor suppressor gene encodes a multidomain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks, 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 histopathologic 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.
AB - The BRCA1 tumor suppressor gene encodes a multidomain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks, 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 histopathologic 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.
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U2 - 10.1158/0008-5472.CAN-21-1415
DO - 10.1158/0008-5472.CAN-21-1415
M3 - Article
C2 - 34548335
AN - SCOPUS:85122458789
VL - 81
SP - 6171
EP - 6182
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 24
ER -