Abstract
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.
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Acknowledgements
We thank M. Grompe, K. Polyak, R. Harris, Q. Waisfisz and J. DeWinter for discussions, and M. Seiden, S. Williams, A. Mes-Massons and S. Chaney for cell lines. This work was supported by National Institutes of Health grants RO1HL52725, RO1 DK43889, P0150654 and PO1HL54785 (to A.D.D.) and by the Doris Duke charitable foundation. T. T. is a Scholar Fellow of the American Society of Hematology.
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Taniguchi, T., Tischkowitz, M., Ameziane, N. et al. Disruption of the Fanconi anemia–BRCA pathway in cisplatin-sensitive ovarian tumors. Nat Med 9, 568–574 (2003). https://doi.org/10.1038/nm852
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DOI: https://doi.org/10.1038/nm852
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