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

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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.

Authors

Rinske Drost, Kiranjit K. Dhillon, Hanneke van der Gulden, Ingrid van der Heijden, Inger Brandsma, Cristina Cruz, Dafni Chondronasiou, Marta Castroviejo-Bermejo, Ute Boon, Eva Schut, Eline van der Burg, Ellen Wientjens, Mark Pieterse, Christiaan Klijn, Sjoerd Klarenbeek, Fabricio Loayza-Puch, Ran Elkon, Liesbeth van Deemter, Sven Rottenberg, Marieke van de Ven, Dick H.W. Dekkers, Jeroen A.A. Demmers, Dik C. van Gent, Reuven Agami, Judith Balmaña, Violeta Serra, Toshiyasu Taniguchi, Peter Bouwman, Jos Jonkers