BRCA1 super( 185delAG) tumors may acquire therapy resistance through expression of RING-less BRCA1

• Published in: The Journal of clinical investigation Vol. 126; no. 8; p. 2903
• Main Authors: Drost, Rinske, Dhillon, Kiranjit K, van der Gulden, Hanneke, van der Heijden, Ingrid, Brandsma, Inger, Cruz, Cristina, Chondronasiou, Dafni, Castroviejo-Bermejo, Marta, Boon, Ute, Schut, Eva, van der Burg, Eline, Wientjens, Ellen, Pieterse, Mark, Klijn, Christiaan, Klarenbeek, Sjoerd, Loayza-Puch, Fabricio, Elkon, Ran, van Deemter, Liesbeth, Rottenberg, Sven, van de Ven, Marieke, Dekkers, Dick H W, Demmers, Jeroen A A, van Gent, Dik C, Agami, Reuven, Balmana, Judith, Serra, Violeta, Taniguchi, Toshiyasu, Bouwman, Peter, Jonkers, Jos
• Format: Journal Article
• Language: English
• Published: 01.08.2016
• ISSN: 0021-9738
• DOI: 10.1172/JCI70196

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 Brca1 super( 185stop) and Brca1 super( 5382stop) alleles, which respectively mimic the 2 most common BRCA1 founder mutations, BRCA1 super( 185delAG) and BRCA1 super( 5382insC). Both the Brca1 super( 185stop) and Brca1 super( 5382stop) mutations predisposed animals to mammary tumors, but Brca1 super( 185stop) tumors responded markedly worse to HRD-targeted therapy than did Brca1 super( 5382stop) tumors. Mice expressing Brca1 super( 185stop) mutations also developed therapy resistance more rapidly than did mice expressing Brca1 super( 5382stop). We determined that both murine Brca1 super( 185stop) tumors and human BRCA1 super( 185delAG) 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.