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.

Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression

“…The possible existence of an ATM-dependent surveillance system for Bcl-2 in breast cancer development is consistent with recent findings showing that activation of ATM is an early event in lung and bladder cancer initiation, and that attenuation of ATM function promotes the cancer progression (Bartkova et al, 2005;Gorgoulis et al, 2005). The proposed mechanism for ATM activation in lung and bladder tumorigenesis is DNA replication stress imposed by abnormal cell cycle progression, which produces DNA damage and therefore activation of ATM.…”

“…Ataxia telangiectasia mutated protein signaling contributes to oncogenemediated activation of p14 ARF -p53 (Li et al, 2004). Oncogene-driven abnormal cell-cycle progression was found to activate ATM in precancerous lesions of the lung and bladder and attenuation of this ATM surveillance system facilitates cancer development (Bartkova et al, 2005;Gorgoulis et al, 2005). In breast cancer, phosporylation of Chk2 at the ATM phosphorylation site, Thr68, was detected in the absence of irradiation (DiTullio et al, 2002).…”

Areca nut exposure increases secretion of tumor‐promoting cytokines in gingival fibroblasts that trigger DNA damage in oral keratinocytes

“…The present study detected 8‐oxoG as evidence of oxidative DNA damage, based on the notion that an oxidative stress‐induced DNA damage pathway underlies its significance at the earliest stages of cancer development 32, 33, 34. The oxidized guanine bases were elevated in various human cancers and thus, oxidative DNA damage is expected to be an etiology of human cancers 35, 36.…”

The predictive value of molecular markers (p53, EGFR, ATM, CHK2) in multimodally treated squamous cell carcinoma of the oesophagus

“…Several substrates of ATM kinase are involved in radiation-induced cell-cycle arrest at the G 1 checkpoint, -for example, p53, Mdm2 and CHK2. Moreover, constitutive activation of ATM and CHK2 has recently been demonstrated in a subset of malignant tumours (Bartkova et al, 2005). It is therefore tempting to speculate that the activation status of ATM and CHK2 may significantly interfere with the radiosensitivity and/or chemosensitivity of tumour cells (Kastan and Bartek, 2004).…”

“…Detailed data on the antibodies are given in Table 1. For three of the four proteins being analysed -that is, p53, ATM, and CHK2 -antibodies were used that detect phosphorylation at specific amino-acid residues that indicate functional activity (ATM, CHK2) (Bakkenist and Kastan 2003;Bartkova et al, 2005) or resistance against inactivation (p53) (Shieh et al, 1997). The reaction was developed using the labelled streptavidinbiotin -alkaline phosphatase system, with fast red as chromogen.…”