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The promise of genetically engineered mice for cancer prevention studies

Key Points

  • Identifying effective cancer chemopreventive agents will significantly reduce cancer morbidity and mortality, especially in high-risk individuals.

  • Genetically engineered mouse (GEM) models of cancer must be assessed carefully for their relevance to human disease and for their predictive power for determining a cancer-prevention response in humans.

  • Relatively fast and inexpensive testing of selected compounds can be performed using appropriate mouse models.

  • Stage-specific responses to chemopreventive agents can be determined using GEM models, unlike TUMOUR XENOGRAFT models.

  • Combination therapies targeting multiple oncogenic pathways can be performed readily in mouse models.

  • GEM colon cancer models can be used to study the effects of chemopreventive agents on tumours arising from genetic lesions that are associated with multi-step carcinogenesis.

  • Mammary cancer mouse models have demonstrated that certain preventive agents might prevent the transition from pre-invasive to invasive carcinoma.

  • Nutritional supplements that target different molecular pathways are effective in a prostate cancer model.

  • The ultimate goal remains the establishment of improved models that can be used for the predictive testing of preventive responses in humans.

Abstract

Sophisticated genetic technologies have led to the development of mouse models of human cancers that recapitulate important features of human oncogenesis. Many of these genetically engineered mouse models promise to be very relevant and relatively rapid systems for determining the efficacy of chemopreventive agents and their mechanisms of action. The validation of such models for chemoprevention will help the selection of appropriate agents for large-scale clinical trials and allow the testing of combination therapies.

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Figure 1: Scheme for using genetically engineered mouse models for testing preventive agents.
Figure 2: Genetically engineered mouse models of intestinal cancer based on mutations occuring during multi-step oncogenesis.
Figure 3: Molecular pathways relevant to colon cancer prevention in genetically engineered mouse models.
Figure 4: Molecular pathways relevant to mammary cancer prevention in genetically engineered mouse models.

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Acknowledgements

The authors greatly appreciate the constructive comments from Nancy Colburn, Glenn Merlino and Ronald Lubet. We apologize to those whose papers have contributed enormously to the field, but due to space limitations, could not be cited.

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DATABASES

NATIONAL CANCER INSTITUTE

breast cancer

colon cancer

prostate cancer

FURTHER INFORMATION

Colon Cancer Chemoprevention Database (Institut National de la Recherche Agronomique)

Jackson Laboratories

National Cancer Institute caArray Data Portal

National Cancer Institute Division of Cancer Prevention

National Cancer Institute Mouse Models of Human Cancer Consortium

Glossary

CHEMOPREVENTION

The use of natural or synthetic compounds to prevent cancer development or progression.

NSAIDS

Non-steroidal anti-inflammatory drugs reduce the inflammatory response by interfering with the production of the prostaglandins that mediate inflammation.

TUMOUR XENOGRAFT

Human tumour cells grown in immuno-compromised mice.

COMPARATIVE GENOMIC HYBRIDIZATION

A molecular cytogenetic method for identifying the gain or loss of large segments of chromosomal material relative to a normal (reference) genome.

RECOMBINEERING

Technology using phage-based Escherichia coli recombination systems, which allows the rapid introduction of targeted mutations into bacterial artificial chromosome (BAC) clones through homologous recombination. The altered BACs can subsequently be used to generate transgenic mice through microinjection or homologous recombination.

BACTERIAL ARTIFICIAL CHROMOSOME

A bacterial vector that can contain up to 200 kb of genomic DNA.

HOMOLOGOUS RECOMBINATION

Exchange of homologous genetic material between different strands of DNA; this is used to introduce altered genomic pieces of DNA into the germ line of mice.

MISMATCH REPAIR GENES

A set of genes that encode proteins that identify discrepancies between complimentary strands of DNA and correct the error.

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Green, J., Hudson, T. The promise of genetically engineered mice for cancer prevention studies. Nat Rev Cancer 5, 184–198 (2005). https://doi.org/10.1038/nrc1565

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