Functional defects in the fanconi anemia pathway in pancreatic cancer cells.
Biallelic BRCA2-mutations can cause Fanconi anemia and are found in approximately 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 Fanconi-defective 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.
van der Heijden
Michiel S
MS
Department of Oncology, Rm. 464, Cancer Research Building, 1650 Orleans St., Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Brody
Jonathan R
JR
Gallmeier
Eike
E
Cunningham
Steven C
SC
Dezentje
David A
DA
Shen
Dong
D
Hruban
Ralph H
RH
Kern
Scott E
SE
D018797:Cell Cycle Proteins; D002945:Cisplatin / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism; D052218:Fanconi Anemia Complementation Group C Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D052241:Fanconi Anemia Complementation Group G Protein; D051856:Fanconi Anemia Complementation Group Proteins; D016195:G2 Phase / Q000187:drug effects; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects; D009687:Nuclear Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011506:Proteins / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism
D018797:Cell Cycle Proteins; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; C499905:FANCD2 protein, human; C499909:FANCG protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D052241:Fanconi Anemia Complementation Group G Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins; D025801:Ubiquitin; D016685:Mitomycin; D002945:Cisplatin