A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and...

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• The BRCA1 tumor suppressor gene is crucial for DNA repair, particularly homologous recombination repair (HRR).
• Missense variants in BRCA1's coiled-coil domain, which interacts with PALB2, are often classified as variants of uncertain clinical significance (VUS).

Purpose of the Study:

• To investigate the functional and clinical significance of a specific BRCA1 coiled-coil domain missense variant (p.L1363P).
• To determine the impact of this variant on embryonic development, mammary tumor suppression, and therapeutic response.

Main Methods:

• Utilized genetically engineered mouse models to study the Brca1 p.L1363P variant.
• Assessed the interaction between BRCA1 and PALB2, embryonic lethality, mammary tumor development, histopathology, DNA copy number stability, and HRR competency.
• Evaluated tumor response to cisplatin and PARP inhibition.

Main Results:

• The Brca1 p.L1363P variant disrupted the BRCA1-PALB2 interaction, leading to embryonic lethality.
• Mice with the Brca1 p.L1363P variant exhibited accelerated mammary tumor development, similar to Brca1 loss, but with distinct histopathological features and more stable DNA copy numbers.
• Tumors from Brca1 p.L1363P mice were HRR incompetent and sensitive to cisplatin and PARP inhibitors.

Conclusions:

• Provides the first direct evidence that a BRCA1 missense variant outside the RING and BRCT domains can increase breast cancer risk.
• Highlights the critical role of the BRCA1 coiled-coil domain-PALB2 interaction in embryonic development and tumor suppression.
• Demonstrates that BRCA1 variants affecting PALB2 interaction impact HRR deficiency and therapeutic sensitivity in breast cancer.