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Wang Y , Krais JJ , Bernhardy AJ , Nicolas E , Cai KQ , Harrell MI , Kim HH , George E , Swisher EM , Simpkins F , Johnson N
RING domain-deficient BRCA1 promotes PARP inhibitor and platinum resistance
J Clin Invest. 2016 Aug 1;126(8) :3145-57
PMID: 27454289    PMCID: PMC4966309   
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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.
Wang, Yifan Krais, John J Bernhardy, Andrea J Nicolas, Emmanuelle Cai, Kathy Q Harrell, Maria I Kim, Hyoung H George, Erin Swisher, Elizabeth M Simpkins, Fiona Johnson, Neil United States J Clin Invest. 2016 Aug 1;126(8):3145-57. doi: 10.1172/JCI87033. Epub 2016 Jul 25.