RING domain-deficient BRCA1 promotes PARP inhibitor and platinum resistance

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Patients with BRCA1-mutated cancers initially respond to platinum and PARPi therapy, but resistance is a significant clinical issue.
• The BRCA1185delAG mutation is a common inherited mutation thought to produce a nonfunctional BRCA1 protein.

Purpose of the Study:

• To investigate the mechanisms of PARPi and platinum resistance in breast cancer cells with a BRCA1185delAG mutation.
• To determine the role of a specific BRCA1 variant in acquired resistance.

Main Methods:

• Utilized the SUM1315MO2 breast cancer cell line harboring a BRCA1185delAG mutation.
• Analyzed PARPi- and cisplatin-resistant clones for secondary mutations and BRCA1 expression.
• Investigated the function and stability of the identified BRCA1 variant (Rdd-BRCA1) and its interaction with BARD1.
• Assessed the impact of Rdd-BRCA1 overexpression on drug resistance and its presence in patient tumors.

Main Results:

• Acquired PARPi and cisplatin resistance in SUM1315MO2 cells did not involve secondary reversion mutations.
• Resistance was associated with increased expression of a RING domain-deficient BRCA1 protein (Rdd-BRCA1), likely initiated downstream of the frameshift mutation.
• Rdd-BRCA1, unlike full-length BRCA1, does not require BARD1 interaction for stability but retains DNA repair functions (foci formation).
• Ectopic Rdd-BRCA1 expression conferred partial resistance to PARPi and cisplatin.
• Rdd-BRCA1 was detected in recurrent tumors from patients with germline BRCA1185delAG mutations.

Conclusions:

• RING-deficient BRCA1 proteins are hypomorphic and can contribute to PARPi and platinum resistance when expressed at high levels.
• Increased expression of Rdd-BRCA1 is a mechanism underlying treatment resistance in BRCA1-mutated breast cancers.