Therapeutic targeting of BRCA1-mutated breast cancers with agents that activate DNA repair

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-11, Vol.74 (21), p.6205-6215
• Main Authors: Alli, Elizabeth, Solow-Cordero, David, Casey, Stephanie C, Ford, James M
• Format: Article
• Language: English
• Subjects: BRCA1 Protein - antagonists & inhibitors; BRCA1 Protein - genetics; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; DNA Repair - drug effects; DNA Repair - genetics; Female; Germ-Line Mutation; Humans; MCF-7 Cells; Molecular Targeted Therapy; Small Molecule Libraries - administration & dosage; Small Molecule Libraries - chemistry
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-14-1716

Cancers due to germline mutations in the BRCA1 gene tend to lack targets for approved chemoprevention agents. This study aimed at a targeted chemoprevention strategy for BRCA1-associated malignancies. Mutant BRCA1 limits the base-excision DNA repair activity that addresses oxidative DNA damage, the accumulation of which heightens one's risk for cancer. Therefore, we conducted a high-throughput chemical screen to identify drug candidates that could attenuate the inhibitory effects of mutant BRCA1 on this repair activity, thereby describing a new class of DNA repair-activating chemopreventive agents. In the screen design, such drugs functioned by enhancing base-excision DNA repair of oxidative DNA damage in the presence of mutant BRCA1, with minimal cytotoxicity. We identified at least one new agent that decreased malignant properties associated with tumorigenesis, including anchorage-independent growth and tumor progression. This work offers a preclinical proof-of-concept for a wholly new approach to chemoprevention in carriers of BRCA1 mutations as a strategy to reduce the prevalence of BRCA1-associated malignancy.