TY - JOUR
T1 - BRCA1 RING Function Is Essential for Tumor Suppression but Dispensable for Therapy Resistance
AU - Drost, Rinske
AU - Bouwman, Peter
AU - Rottenberg, Sven
AU - Boon, Ute
AU - Schut, Eva
AU - Klarenbeek, Sjoerd
AU - Klijn, Christiaan
AU - van der Heijden, Ingrid
AU - van der Gulden, Hanneke
AU - Wientjens, Ellen
AU - Pieterse, Mark
AU - Catteau, Aurelie
AU - Green, Pete
AU - Solomon, Ellen
AU - Morris, Joanna R.
AU - Jonkers, Jos
PY - 2011/12/13
Y1 - 2011/12/13
N2 - Hereditary breast cancers are frequently caused by germline BRCA1 mutations. The BRCA1(C61G) 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 Brca1(C61G) mutation in a conditional mouse model for BRCA1 -associated breast cancer. In contrast to BRCA1 -deficient mammary carcinomas, tumors carrying the Brca1(C61G) mutation responded poorly to platinum drugs and PARP inhibition and rapidly developed resistance while retaining the Brca1(C61G) mutation. These findings point to hypomorphic activity of the BRCA1-C61G protein that, although unable to prevent tumor development, affects response to therapy.
AB - Hereditary breast cancers are frequently caused by germline BRCA1 mutations. The BRCA1(C61G) 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 Brca1(C61G) mutation in a conditional mouse model for BRCA1 -associated breast cancer. In contrast to BRCA1 -deficient mammary carcinomas, tumors carrying the Brca1(C61G) mutation responded poorly to platinum drugs and PARP inhibition and rapidly developed resistance while retaining the Brca1(C61G) mutation. These findings point to hypomorphic activity of the BRCA1-C61G protein that, although unable to prevent tumor development, affects response to therapy.
U2 - 10.1016/j.ccr.2011.11.014
DO - 10.1016/j.ccr.2011.11.014
M3 - Article
VL - 20
SP - 797
EP - 809
JO - CANCER CELL
JF - CANCER CELL
IS - 6
ER -