TY - JOUR
T1 - Functional defects in the Fanconi anemia pathway in pancreatic cancer cells
AU - Van Der Heijden, Michiel S.
AU - Brody, Jonathan R.
AU - Gallmeier, Eike
AU - Cunningham, Steven C.
AU - Dezentje, David A.
AU - Shen, Dong
AU - Hruban, Ralph H.
AU - Kern, Scott E.
N1 - Funding Information:
Supported by the National Institutes of Health (Specialized Programs of Research Excellence in Gastrointestinal Cancer grant CA 62924 ), the Vrijvrouwe van Renswoude Foundation (to M.S.H.), the VSB Fund (to M.S.H.), and the Deutsche Forschungsgemeinschaft (to E.G.).
PY - 2004/8
Y1 - 2004/8
N2 - Biallelic BRCA2-mutations can cause Fanconi anemia and are found in ∼7% of pancreatic cancers. Recently, several sequence changes in FANCC and FANCG were reported in pancreatic cancer. Functional defects in the Fanconi pathway can result in a marked hypersensitivity to interstrand crosslinking agents, such as mitomycin C. The functional implications of mutations in the Fanconi pathway in cancer have not been fully studied yet; these studies are needed to pave the way for clinical trials of treatment with crosslinking agents of Fanconi-defective cancers. The competence of the proximal Fanconi pathway was screened in 21 pancreatic cancer cell lines by an assay of Fancd2 monoubiquitination using a Fancd2 immunoblot. The pancreatic cancer cell lines Hs766T and PL11 were defective in Fancd2 monoubiquitination. In PL11, this defect led to the identification of a large homozygous deletion in FANCC, the first cancer cell line found to be FANCC-null. The Fanconidefective cell lines Hs766T, PL11, and CAPAN1 were hypersensitive to the crosslinking agent mitomycin C and some to cis-platin, as measured by cell survival assays and G 2/M cell-cycle arrest. These results support the practical exploration of crosslinking agents for non-Fanconi anemia patients that have tumors defective in the Fanconi pathway.
AB - Biallelic BRCA2-mutations can cause Fanconi anemia and are found in ∼7% of pancreatic cancers. Recently, several sequence changes in FANCC and FANCG were reported in pancreatic cancer. Functional defects in the Fanconi pathway can result in a marked hypersensitivity to interstrand crosslinking agents, such as mitomycin C. The functional implications of mutations in the Fanconi pathway in cancer have not been fully studied yet; these studies are needed to pave the way for clinical trials of treatment with crosslinking agents of Fanconi-defective cancers. The competence of the proximal Fanconi pathway was screened in 21 pancreatic cancer cell lines by an assay of Fancd2 monoubiquitination using a Fancd2 immunoblot. The pancreatic cancer cell lines Hs766T and PL11 were defective in Fancd2 monoubiquitination. In PL11, this defect led to the identification of a large homozygous deletion in FANCC, the first cancer cell line found to be FANCC-null. The Fanconidefective cell lines Hs766T, PL11, and CAPAN1 were hypersensitive to the crosslinking agent mitomycin C and some to cis-platin, as measured by cell survival assays and G 2/M cell-cycle arrest. These results support the practical exploration of crosslinking agents for non-Fanconi anemia patients that have tumors defective in the Fanconi pathway.
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U2 - 10.1016/S0002-9440(10)63329-9
DO - 10.1016/S0002-9440(10)63329-9
M3 - Article
C2 - 15277238
AN - SCOPUS:3242789247
SN - 0002-9440
VL - 165
SP - 651
EP - 657
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 2
ER -