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

R Drost, KK Dhillon, H van der Gulden, I van der Heijden, Inger Brandsma, C Cruz, D Chondronasiou, M Castroviejo-Bermejo, U Boon, E Schut, E Burg, E Wientjens, M Pieterse, C Klijn, S Klarenbeek, F Loayza-Puch, R Elkon, L van Deemter, S Rottenberg, M (Marieke) van de VenDick Dekkers, Jeroen Demmers, Dik van Gent, R Agami, J Balmana, V Serra, T Taniguchi, P Bouwman, J Jonkers

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Abstract

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(185stop) and Brca1(5382stop) alleles, which respectively mimic the 2 most common BRCA1 founder mutations, BRCA1(185delAG) and BRCA1(5382insC). Both the Brca1(185stop) and Brca1(5382stop) mutations predisposed animals to mammary tumors, but Brca1(185stop) tumors responded markedly worse to HRD-targeted therapy than did Brca1(5382stop) tumors. Mice expressing Brca1(185stop) mutations also developed therapy resistance more rapidly than did mice expressing Brca1(5382stop). We determined that both murine Brca1(185stop) tumors and human BRCA1(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.
Original languageUndefined/Unknown
Pages (from-to)2903-2918
Number of pages16
JournalJournal of Clinical Investigation
Volume126
Issue number8
DOIs
Publication statusPublished - 2016

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