title: RING domain-deficient BRCA1 promotes PARP inhibitor and platinum resistance.
abstract: Patients with cancers that harbor breast cancer 1 (BRCA1) mutations initially respond well to platinum and poly(ADP-ribose) polymerase inhibitor (PARPi) therapy; however, resistance invariably arises in these patients and is a major clinical problem. The BRCA1185delAG allele is a common inherited mutation located close to the protein translation start site that is thought to produce a shortened, nonfunctional peptide. In this study, we investigated the mechanisms that lead to PARPi and platinum resistance in the SUM1315MO2 breast cancer cell line, which harbors a hemizygous BRCA1185delAG mutation. SUM1315MO2 cells were initially sensitive to PARPi and cisplatin but readily acquired resistance. PARPi- and cisplatin-resistant clones did not harbor secondary reversion mutations; rather, PARPi and platinum resistance required increased expression of a really interesting gene (RING) domain-deficient BRCA1 protein (Rdd-BRCA1). Initiation of translation occurred downstream of the frameshift mutation, probably at the BRCA1-Met-297 codon. In contrast to full-length BRCA1, Rdd-BRCA1 did not require BRCA1-associated RING domain 1 (BARD1) interaction for stability. Functionally, Rdd-BRCA1 formed irradiation-induced foci and supported RAD51 foci formation. Ectopic overexpression of Rdd-BRCA1 promoted partial PARPi and cisplatin resistance. Furthermore, Rdd-BRCA1 protein expression was detected in recurrent carcinomas from patients who carried germline BRCA1185delAG mutations. Taken together, these results indicate that RING-deficient BRCA1 proteins are hypomorphic and capable of contributing to PARPi and platinum resistance when expressed at high levels.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Wang
authors.forename: John J
authors.initials: JJ
authors.lastname: Krais
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Bernhardy
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Nicolas
authors.forename: Kathy Q
authors.initials: KQ
authors.lastname: Cai
authors.forename: Maria I
authors.initials: MI
authors.lastname: Harrell
authors.forename: Hyoung H
authors.initials: HH
authors.lastname: Kim
authors.forename: Erin
authors.initials: E
authors.lastname: George
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Swisher
authors.forename: Fiona
authors.initials: F
authors.lastname: Simpkins
authors.forename: Neil
authors.initials: N
authors.lastname: Johnson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D019313:BRCA1 Protein / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D064113:CRISPR-Cas Systems; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005091:Exons; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D009154:Mutation; D009368:Neoplasm Transplantation; D010984:Platinum / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000072417:Protein Domains
chemical_list: D000911:Antibodies, Monoclonal; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D010984:Platinum; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin