title: BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance.
abstract: Hereditary breast cancers are frequently caused by germline BRCA1 mutations. The BRCA1(C61G) mutation in the BRCA1 RING domain is a common pathogenic missense variant, which reduces BRCA1/BARD1 heterodimerization and abrogates its ubiquitin ligase activity. To investigate the role of BRCA1 RING function in tumor suppression and therapy response, we introduced the Brca1(C61G) mutation in a conditional mouse model for BRCA1-associated breast cancer. In contrast to BRCA1-deficient mammary carcinomas, tumors carrying the Brca1(C61G) mutation responded poorly to platinum drugs and PARP inhibition and rapidly developed resistance while retaining the Brca1(C61G) mutation. These findings point to hypomorphic activity of the BRCA1-C61G protein that, although unable to prevent tumor development, affects response to therapy.
authors.affiliation: Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam.
authors.forename: Rinske
authors.initials: R
authors.lastname: Drost
authors.forename: Peter
authors.initials: P
authors.lastname: Bouwman
authors.forename: Sven
authors.initials: S
authors.lastname: Rottenberg
authors.forename: Ute
authors.initials: U
authors.lastname: Boon
authors.forename: Eva
authors.initials: E
authors.lastname: Schut
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Klarenbeek
authors.forename: Christiaan
authors.initials: C
authors.lastname: Klijn
authors.forename: Ingrid
authors.initials: I
authors.lastname: van der Heijden
authors.forename: Hanneke
authors.initials: H
authors.lastname: van der Gulden
authors.forename: Ellen
authors.initials: E
authors.lastname: Wientjens
authors.forename: Mark
authors.initials: M
authors.lastname: Pieterse
authors.forename: Aurelie
authors.initials: A
authors.lastname: Catteau
authors.forename: Pete
authors.initials: P
authors.lastname: Green
authors.forename: Ellen
authors.initials: E
authors.lastname: Solomon
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Morris
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D055786:Gene Knockout Techniques; D042822:Genomic Instability; D053533:Keratin-8 / Q000378:metabolism; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009368:Neoplasm Transplantation; D010793:Phthalazines / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D053533:Keratin-8; C486595:Krt8 protein, mouse; D010793:Phthalazines; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin; C531550:olaparib