title: DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis.
abstract: During the evolution of cancer, the incipient tumour experiences 'oncogenic stress', which evokes a counter-response to eliminate such hazardous cells. However, the nature of this stress remains elusive, as does the inducible anti-cancer barrier that elicits growth arrest or cell death. Here we show that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions (but not normal tissues) commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and Chk2, and phosphorylated histone H2AX and p53. Similar checkpoint responses were induced in cultured cells upon expression of different oncogenes that deregulate DNA replication. Together with genetic analyses, including a genome-wide assessment of allelic imbalances, our data indicate that early in tumorigenesis (before genomic instability and malignant conversion), human cells activate an ATR/ATM-regulated DNA damage response network that delays or prevents cancer. Mutations compromising this checkpoint, including defects in the ATM-Chk2-p53 pathway, might allow cell proliferation, survival, increased genomic instability and tumour progression.
authors.affiliation: Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. jb@cancer.dk
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Horejsí
authors.forename: Karen
authors.initials: K
authors.lastname: Koed
authors.forename: Alwin
authors.initials: A
authors.lastname: Krämer
authors.forename: Frederic
authors.initials: F
authors.lastname: Tort
authors.forename: Karsten
authors.initials: K
authors.lastname: Zieger
authors.forename: Per
authors.initials: P
authors.lastname: Guldberg
authors.forename: Maxwell
authors.initials: M
authors.lastname: Sehested
authors.forename: Jahn M
authors.initials: JM
authors.lastname: Nesland
authors.forename: Claudia
authors.initials: C
authors.lastname: Lukas
authors.forename: Torben
authors.initials: T
authors.lastname: Ørntoft
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
mesh_terms: D022981:Allelic Imbalance / Q000235:genetics; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D064447:Checkpoint Kinase 2; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050684:E2F Transcription Factors; D004789:Enzyme Activation; D016158:Genes, p53 / Q000235:genetics; D042822:Genomic Instability; D006801:Humans; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D009857:Oncogenes / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D014157:Transcription Factors; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases