title: BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1.
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 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.
authors.forename: Rinske
authors.initials: R
authors.lastname: Drost
authors.forename: Kiranjit K
authors.initials: KK
authors.lastname: Dhillon
authors.forename: Hanneke
authors.initials: H
authors.lastname: van der Gulden
authors.forename: Ingrid
authors.initials: I
authors.lastname: van der Heijden
authors.forename: Inger
authors.initials: I
authors.lastname: Brandsma
authors.forename: Cristina
authors.initials: C
authors.lastname: Cruz
authors.forename: Dafni
authors.initials: D
authors.lastname: Chondronasiou
authors.forename: Marta
authors.initials: M
authors.lastname: Castroviejo-Bermejo
authors.forename: Ute
authors.initials: U
authors.lastname: Boon
authors.forename: Eva
authors.initials: E
authors.lastname: Schut
authors.forename: Eline
authors.initials: E
authors.lastname: van der Burg
authors.forename: Ellen
authors.initials: E
authors.lastname: Wientjens
authors.forename: Mark
authors.initials: M
authors.lastname: Pieterse
authors.forename: Christiaan
authors.initials: C
authors.lastname: Klijn
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Klarenbeek
authors.forename: Fabricio
authors.initials: F
authors.lastname: Loayza-Puch
authors.forename: Ran
authors.initials: R
authors.lastname: Elkon
authors.forename: Liesbeth
authors.initials: L
authors.lastname: van Deemter
authors.forename: Sven
authors.initials: S
authors.lastname: Rottenberg
authors.forename: Marieke
authors.initials: M
authors.lastname: van de Ven
authors.forename: Dick H W
authors.initials: DH
authors.lastname: Dekkers
authors.forename: Jeroen A A
authors.initials: JA
authors.lastname: Demmers
authors.forename: Dik C
authors.initials: DC
authors.lastname: van Gent
authors.forename: Reuven
authors.initials: R
authors.lastname: Agami
authors.forename: Judith
authors.initials: J
authors.lastname: Balmaña
authors.forename: Violeta
authors.initials: V
authors.lastname: Serra
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Peter
authors.initials: P
authors.lastname: Bouwman
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
mesh_terms: D000483:Alleles; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D002945:Cisplatin / Q000494:pharmacology; D003433:Crosses, Genetic; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D018703:Founder Effect; D016368:Frameshift Mutation; D017353:Gene Deletion; D005818:Genetic Engineering; D006801:Humans; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011995:Recombination, Genetic
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D010793:Phthalazines; D010879:Piperazines; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin; C531550:olaparib