TY - JOUR AU - Drost, Rinske AU - Dhillon, Kiranjit K. AU - van der Gulden, Hanneke AU - van der Heijden, Ingrid AU - Brandsma, Inger AU - Cruz, Cristina AU - Chondronasiou, Dafni AU - Castroviejo-Bermejo, Marta AU - Boon, Ute AU - Schut, Eva AU - van der Burg, Eline AU - Wientjens, Ellen AU - Pieterse, Mark AU - Klijn, Christiaan AU - Klarenbeek, Sjoerd AU - Loayza-Puch, Fabricio AU - Elkon, Ran AU - van Deemter, Liesbeth AU - Rottenberg, Sven AU - van de Ven, Marieke AU - Dekkers, Dick H.W. AU - Demmers, Jeroen A.A. AU - van Gent, Dik C. AU - Agami, Reuven AU - Balmaña, Judith AU - Serra, Violeta AU - Taniguchi, Toshiyasu AU - Bouwman, Peter AU - Jonkers, Jos T1 - BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1 PY - 2016/08/01/ AB - Heterozygous germline mutations in breast cancer 1 (BRCA1) strongly predispose women to breast cancer. BRCA1 plays an important role in DNA double-strand break (DSB) repair via homologous recombination (HR), which is important for tumor suppression. Although BRCA1-deficient cells are highly sensitive to treatment with DSB-inducing agents through their HR deficiency (HRD), BRCA1-associated tumors display heterogeneous responses to platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors in clinical trials. It is unclear whether all pathogenic BRCA1 mutations have similar effects on the response to therapy. Here, we have investigated mammary tumorigenesis and therapy sensitivity in mice carrying the Brca1185stop and Brca15382stop alleles, which respectively mimic the 2 most common BRCA1 founder mutations, BRCA1185delAG and BRCA15382insC. Both the Brca1185stop and Brca15382stop mutations predisposed animals to mammary tumors, but Brca1185stop tumors responded markedly worse to HRD-targeted therapy than did Brca15382stop tumors. Mice expressing Brca1185stop mutations also developed therapy resistance more rapidly than did mice expressing Brca15382stop. We determined that both murine Brca1185stop tumors and human BRCA1185delAG breast cancer cells expressed a really interesting new gene domain–less (RING-less) BRCA1 protein that mediated resistance to HRD-targeted therapies. Together, these results suggest that expression of RING-less BRCA1 may serve as a marker to predict poor response to DSB-inducing therapy in human cancer patients. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI70196 VL - 126 IS - 8 UR - https://doi.org/10.1172/JCI70196 SP - 2903 EP - 2918 PB - The American Society for Clinical Investigation ER -