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.
Bibliographical noteFunding 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.
© 2021 American Association for Cancer Research