Author/Authors :
Drost، نويسنده , , Rinske and Bouwman، نويسنده , , Peter and Rottenberg، نويسنده , , Sven and Boon، نويسنده , , Ute and Schut، نويسنده , , Eva and Klarenbeek، نويسنده , , Sjoerd and Klijn، نويسنده , , Christiaan and van der Heijden، نويسنده , , Ingrid and van der Gulden، نويسنده , , Hanneke and Wientjens، نويسنده , , Ellen and Pieterse، نويسنده , , Mark and Catteau، نويسنده , , Aurelie and Green، نويسنده , , Pete and Solomon، نويسنده , , Ellen and Morris، نويسنده , , Joanna R. and Jonkers، نويسنده , , Jos، نويسنده ,
Abstract :
Summary
tary breast cancers are frequently caused by germline BRCA1 mutations. The BRCA1C61G mutation in the BRCA1 RING domain is a common pathogenic missense variant, which reduces BRCA1/BARD1 heterodimerization and abrogates its ubiquitin ligase activity. To investigate the role of BRCA1 RING function in tumor suppression and therapy response, we introduced the Brca1C61G mutation in a conditional mouse model for BRCA1-associated breast cancer. In contrast to BRCA1-deficient mammary carcinomas, tumors carrying the Brca1C61G mutation responded poorly to platinum drugs and PARP inhibition and rapidly developed resistance while retaining the Brca1C61G mutation. These findings point to hypomorphic activity of the BRCA1-C61G protein that, although unable to prevent tumor development, affects response to therapy.
