DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis

Jirina Bartkova (), Zuzana Hořejší, Karen Koed, Alwin Krämer, Frederic Tort, Karsten Zieger, Per Guldberg, Maxwell Sehested, Jahn M. Nesland, Claudia Lukas, Torben Ørntoft, Jiri Lukas and Jiri Bartek ()
Additional contact information
Jirina Bartkova: Danish Cancer Society
Zuzana Hořejší: Danish Cancer Society
Karen Koed: Aarhus University Hospital, Skejby
Alwin Krämer: Danish Cancer Society
Frederic Tort: Danish Cancer Society
Karsten Zieger: Aarhus University Hospital, Skejby
Per Guldberg: Danish Cancer Society
Maxwell Sehested: University Hospital
Jahn M. Nesland: University of Oslo
Claudia Lukas: Danish Cancer Society
Torben Ørntoft: Aarhus University Hospital, Skejby
Jiri Lukas: Danish Cancer Society
Jiri Bartek: Danish Cancer Society

Nature, 2005, vol. 434, issue 7035, 864-870

Abstract: 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.

Date: 2005
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DOI: 10.1038/nature03482

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