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

@article{Brtkov2005DNADR,
  title={DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis},
  author={Jiřina B{\'a}rtkov{\'a} and Zuzana Hořej{\vs}{\'i} and Karen Koed and Alwin Kr{\"a}mer and Frederic Tort and Karsten A E Zieger and Per Guldberg and Maxwell Sehested and Jahn Marthin Nesland and Claudia Lukas and Torben F. {\O}rntoft and Jiri Lukas and Jiri Bartek},
  journal={Nature},
  year={2005},
  volume={434},
  pages={864-870}
}
During the evolution of cancer, the incipient tumour experiences ‘oncogenic stress’, which evokes a counter-response to eliminate such hazardous cells. [] Key Result 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…

DNA Damage Response as an Anti-Cancer Barrier: Damage Threshold and the Concept of 'Conditional Haploinsufficiency'

TLDR
It is proposed that carriers of such DDR defects may be more prone to malignancy due to ‘conditional haploinsufficiency’: such partial defect may be asymptomatic in normal tissues, yet they may become manifest under conditions of supra-threshold endogenous DNA damage in oncogene-driven pre-malignant lesions.

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  • Biology, Medicine
    Cancer research
  • 2015
TLDR
The potential existence of distinct DNA damage thresholds at various stages of tumorigenesis and what the ramifications of such thresholds would be are discussed, including the ambiguous role of the DDR pathway in human cancers, therapy-induced malignancies, and enhanced therapies.

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TLDR
It is proposed that relative to DDR activation, ARF provides a complementary and delayed barrier to tumor development, responding to more robust stimuli of escalating oncogenic overload.

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TLDR
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Genetic changes and DNA damage responses in the prostate

TLDR
This review discusses the relevance of prostatic epithelial cells in prostate tumourigenesis and highlights common molecular changes associated with prostate cancer, and DNA damage responses of primary cultures of human prostatic and fresh human prostate tissues are discussed providing evidence for alterations in crucial DNA damage checkpoint molecules.

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TLDR
Recent advances in DNA damage response are highlighted, with particular emphasis on mechanistic insights, emerging issues of special conceptual significance and discussion of major remaining challenges and implications of the concept of DDR as a tumorigenesis barrier for experimental and clinical oncology.

Suppression of Akt-mTOR Pathway-A Novel Component of Oncogene Induced DNA Damage Response Barrier in Breast Tumorigenesis

TLDR
The data suggest that AKT-mTOR pathway is a novel component of oncogene induced DNA damage response in immortalized ‘normal-like’ breast cells and its suppression may contribute to growth arrest and arrest of the breast tumorigenesis.

Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions

TLDR
It is proposed that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations.

The pathological response to DNA damage does not contribute to p53-mediated tumour suppression

TLDR
It is shown that the p53-mediated pathological response to whole-body irradiation, a prototypical genotoxic carcinogen, is irrelevant for suppression of radiation-induced lymphoma, and delaying the restoration of p53 function until the acute radiation response has subsided abrogates all of the radiation- induced pathology yet preserves much of the protection from lymphoma.

Medicine: Aborting the birth of cancer

TLDR
It is found that early stages of cancer development are associated with an active DNA damage response and p53-dependent cell death, and activation of the DNA damage checkpoint occurs before chromosome instability and malignancy.
...

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