A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair

Emilia M. Pulver, Chirantani Mukherjee, Gerarda van de Kamp, Stefan J. Roobol, Magdalena B. Rother, Hanneke van der Gulden, Roebi de Bruijn, Maria Valeria Lattanzio, Eline van der Burg, Anne Paulien Drenth, Nicole S. Verkaik, Kerstin Hahn, Sjoerd Klarenbeek, Renske de Korte-Grimmerink, Marieke van de Ven, Colin E.J. Pritchard, Ivo J. Huijbers, Bing Xia, Dik C. van Gent, Jeroen EssersHaico van Attikum, Arnab Ray Chaudhuri, Peter Bouwman*, Jos Jonkers

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)6171-6182
Number of pages12
JournalCancer Research
Volume81
Issue number24
DOIs
Publication statusPublished - 15 Dec 2021

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