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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.

Pubmed ID: 12692539

Authors

  • Taniguchi T
  • Tischkowitz M
  • Ameziane N
  • Hodgson SV
  • Mathew CG
  • Joenje H
  • Mok SC
  • D'Andrea AD

Journal

Nature medicine

Publication Data

May 1, 2003

Associated Grants

  • Agency: PHS HHS, Id: P0150654
  • Agency: NHLBI NIH HHS, Id: P01HL54785
  • Agency: NIDDK NIH HHS, Id: R01 DK43889
  • Agency: NHLBI NIH HHS, Id: R01HL52725

Mesh Terms

  • Cisplatin
  • DNA Methylation
  • Drug Resistance, Neoplasm
  • Fanconi Anemia Complementation Group F Protein
  • Female
  • Genes, BRCA1
  • Genes, BRCA2
  • Humans
  • Ovarian Neoplasms
  • RNA-Binding Proteins
  • Tumor Cells, Cultured