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.
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.
Michiel S
MS
van der Heijden
Jonathan R
JR
Brody
Eike
E
Gallmeier
Steven C
SC
Cunningham
David A
DA
Dezentje
Dong
D
Shen
Ralph H
RH
Hruban
Scott E
SE
Kern
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