title: Therapeutic targeting of BRCA1-mutated breast cancers with agents that activate DNA repair.
abstract: 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.
authors.affiliation: Department of Medicine/Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Alli
authors.affiliation: Department of Chemical and Systems Biology and Stanford High-Throughput Bioscience Center, Stanford University School of Medicine, Stanford, California.
authors.forename: David
authors.initials: D
authors.lastname: Solow-Cordero
authors.affiliation: Department of Medicine/Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Casey
authors.affiliation: Department of Medicine/Oncology, Stanford University School of Medicine, Stanford, California. Department of Genetics, Stanford University School of Medicine, Stanford, California. jmf@stanford.edu.
authors.forename: James M
authors.initials: JM
authors.lastname: Ford
mesh_terms: D019313:BRCA1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D061986:MCF-7 Cells; D058990:Molecular Targeted Therapy; D054852:Small Molecule Libraries / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D019313:BRCA1 Protein; D054852:Small Molecule Libraries