title: BRCA1 and HSP90 cooperate in homologous and non-homologous DNA double-strand-break repair and G2/M checkpoint activation.
abstract: Expression of functional breast cancer susceptibility gene 1 (BRCA1) in human breast and ovarian cancers is associated with resistance to platinum-based chemotherapeutics and poly(ADP ribose) polymerase (PARP) inhibitors. BRCA1 is a nuclear tumor suppressor that is critical for resolving double-strand DNA breaks (DSBs) and interstrand crosslinks (ICLs) by homologous recombination (HR). In vitro, animal and human clinical data have demonstrated that BRCA1-deficient cancers are highly sensitive to ICL-inducing chemotherapeutic agents, are amenable to synthetic lethal approaches that exploit defects in DSB/ICL repair, and may be associated with improved survival. Conversely, high or restored expression of BRCA1 in breast and ovarian cancer is associated with therapeutic resistance and poor prognosis. There has been much interest in identifying agents that interfere with BRCA1-dependent DSB/ICL repair to restore or enhance sensitivity to cancer therapeutics. We demonstrate that the heat-shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin [17-AAG (Tanespimycin)], currently in Phase II/III clinical evaluation for several cancers, induces BRCA1 ubiquitination and proteasomal degradation, resulting in compromised repair of ionizing radiation- and platinum-induced DNA damage. We show that loss of HSP90 function abolishes BRCA1-dependent DSB repair and that BRCA1-deficient cells are hypersensitive to 17-AAG due to impaired Gap 2/Mitosis (G2/M) checkpoint activation and resultant mitotic catastrophe. In summary, we document an upstream HSP90-dependent regulatory point in the Fanconi anemia/BRCA DSB/ICL repair pathway, illuminate the role of BRCA1 in regulating damage-associated checkpoint and repair responses to HSP90 inhibitors, and identify BRCA1 as a clinically relevant target for enhancing sensitivity in refractory and/or resistant malignancies.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Shane R
authors.initials: SR
authors.lastname: Stecklein
authors.forename: Easwari
authors.initials: E
authors.lastname: Kumaraswamy
authors.forename: Fariba
authors.initials: F
authors.lastname: Behbod
authors.forename: Wenjia
authors.initials: W
authors.lastname: Wang
authors.forename: Vamsee
authors.initials: V
authors.lastname: Chaguturu
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Harlan-Williams
authors.forename: Roy A
authors.initials: RA
authors.lastname: Jensen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D019313:BRCA1 Protein / Q000235:genetics* / Q000502:physiology*; D016227:Benzoquinones / Q000494:pharmacology; D002455:Cell Division; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D016195:G2 Phase; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D059765:Homologous Recombination; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D016227:Benzoquinones; D003432:Cross-Linking Reagents; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin