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Review
. 2012 Jan 19;12(2):144-9.
doi: 10.1038/nrc3206.

Mouse models of cancer: does the strain matter?

Kent W Hunter  1
Affiliations
Review

Mouse models of cancer: does the strain matter?

Kent W Hunter. Nat Rev Cancer. .

Abstract

Mouse models are indispensible tools for understanding the molecular basis of cancer. However, despite the invaluable data provided regarding tumour biology, owing to inbreeding, current mouse models fail to accurately model human populations. Polymorphism is the essential characteristic that makes each of us unique humans, with different disease susceptibility, presentation and progression. Therefore, as we move closer towards designing clinical treatment that is based on an individual's unique biological makeup, it is imperative that we understand how inherited variability influences cancer phenotypes, how it can confound experiments and how it can be exploited to reveal new truths about cancer biology.

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Figures

Figure 1:
Figure 1:
Potential genomic structures of genetically engineered mice, based on an albino embryonic stem (ES) cell line. The chimeric founder, after injection of albino ES cells into a C57BL/6 recipient blastocyst, is shown in the upper right. Germline transmission of the engineered chromosome (vertical rectangles) is performed by breeding the chimeric founder to a mouse with a different coat color. Coat color is indicated by the mouse cartoon. Percentage of the genome from the ES donor strain and recipient strains are depicted by the circles below the chromosome boxes. Since albinism is recessive, the F1 progeny is crossed back to an albino mouse. Generation of white mice in the second generation indicates successful germline transmission of the ES cell genome (dashed box). Note that the coat color mutation is usually not linked to the engineered locus and therefore they will segregate independently in the progeny. These mice will carry not only the engineered locus (indicated by the asterisk) but also 25% of the black genome. Repeated crossing of the engineered locus back to the black strain results in a congenic animal that is homozygous black for the entire genome except the region surrounding the locus of interest. Repeated brother-sister mating to carry the construct of interest homozygously without first generating congenics can result in novel inbred (recombinant congenic) strains that are composites of the ES cell donor and recipient genomes.
Figure 2:
Figure 2:
Strategies to generate Recombinant Inbred (RI) panels and the Collaborative Cross. A) Mating strategy to generate a standard RI panel. The chromosomes of the maternal strain are depicted by the tan ovals. The paternal strain chromosomes are black. Mitrochondrial genomes are depicted by circles with M’s. The resulting RI panel substrains are inbred chimeras of the original two parental strains, as indicated at the bottom of the figure. RI panels usually consist of 13–75 substrains (RI strains – The Jackson Laboratory, http://www.jax.org/smsr/ristrain.html) (Box 1). B) The eight-way funnel breeding design of the Collaborative Cross. One example of the funnel design is shown here. Additional funnels are generated by changing the position of the parental strains at the top of the funnel. The genomes of each of the eight progenitor strains are indicated by colored boxes. The funnel design incorporates all eight genomes randomly until inbreeding begins after the G2:F1 generation. The ultimate goal of the CC is to generate more than a hundred sublines. Current status of the CC can be found at the Collaborative Cross Status website (http://csbio.unc.edu/CCstatus/index.py).
Figure 3:
Figure 3:
Mating strategies for mapping cancer modifiers of GEM models using the Collaborative Cross. A) Dominant transgene or haploinsufficient GEM strategy. GEM models are bred to the individual CC lines and phenotyped. Modifier genes are identified by comparing the phenotypes of each F1 to the known haplotypes of each CC line. B) Mating strategy for recessive GEM models. The GEM model is bred to CC lines to generate F1 animals, which are then intercrossed (left) or backcrossed (right) to the GEM model to produce homozygous knockouts. Due to the segregation of the CC genome in these animals, a small population is phenotyped to generate an median phenotype value for that population, based on both the segregating background and the engineered locus for each CC line. C) Genetic mapping for recessive GEM models. Each of the CC x GEM crosses produced as shown in figure 3B would produce a population with a distribution of the phenotype in question. The median phenotypic value of each CC x GEM cross, however, would likely be different depending on the complement of modifiers introduced by each CC line. These median values for each cross can then be used as a “meta-phenotype” to map modifiers that influenced the median phenotype value by comparison to the CC parental genotypes. No additional genotyping is required for this. Additional linkage information can be obtained by performing genotyping any of the CC x GEM crosses to further map and/or refine modifiers present in any particular CC subline of interest.
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