Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors.
Ovarian tumor cells are often genomically unstable and hypersensitive to cisplatin. To understand the molecular basis for this phenotype, we examined the integrity of the Fanconi anemia-BRCA (FANC-BRCA) pathway in those cells. This pathway regulates cisplatin sensitivity and is governed by the coordinate activity of six genes associated with Fanconi anemia (FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG) as well as BRCA1 and BRCA2 (FANCD1). Here we show that the FANC-BRCA pathway is disrupted in a subset of ovarian tumor lines. Mono-ubiquitination of FANCD2, a measure of the function of this pathway, and cisplatin resistance were restored by functional complementation with FANCF, a gene that is upstream in this pathway. FANCF inactivation in ovarian tumors resulted from methylation of its CpG island, and acquired cisplatin resistance correlated with demethylation of FANCF. We propose a model for ovarian tumor progression in which the initial methylation of FANCF is followed by FANCF demethylation and ultimately results in cisplatin resistance.
Taniguchi
Toshiyasu
T
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Guy's King's and St. Thomas' School of Medicine, London, UK.
Tischkowitz
Marc
M
Ameziane
Najim
N
Hodgson
Shirley V
SV
Mathew
Christopher G
CG
Joenje
Hans
H
Mok
Samuel C
SC
D'Andrea
Alan D
AD
D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D052219:Fanconi Anemia Complementation Group F Protein; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D014407:Tumor Cells, Cultured
C499901:FANCF protein, human; D052219:Fanconi Anemia Complementation Group F Protein; D016601:RNA-Binding Proteins; D002945:Cisplatin