Abstract
Chromosomal common fragile sites (CFSs) are specific mammalian genomic regions that show an increased frequency of gaps and breaks when cells are exposed to replication stress in vitro. CFSs are also consistently involved in chromosomal abnormalities in vivo related to cancer. Interestingly, several CFSs contain one or more tumor suppressor genes whose structure and function are often affected by chromosomal fragility. The two most active fragile sites in the human genome are FRA3B and FRA16D where the tumor suppressor genes FHIT and WWOX are located, respectively. The best approach to study tumorigenic effects of altered tumor suppressors located at CFSs in vivo is to generate mouse models in which these genes are inactivated. This paper summarizes our present knowledge on mouse models of cancer generated by knocking out tumor suppressors of CFS.
Highlights
Fragile sites can be defined as heritable-specific loci on human chromosomes that exhibit nonrandom gaps or breaks when chromosomes are exposed to specific cell culture conditions [1]
Other common fragile sites have been implicated in homozygous deletions or loss of heterozygosity (LOH) observed in various malignancies [1]: FRA16D, located on chromosome 16q23.2 and altered in breast [18], prostate [19], and hepatocellular carcinoma [20]; FRA6E on 6q26 [21], and FRA7G on 7q31.2 [22], both altered in ovarian cancer among others
A number of knock-out and transgenic mouse models have been generated to study the in vivo functions of tumor suppressor genes mapping on common fragile sites (CFSs): some of them presented a phenotype associated with pathophysiological abnormalities, whereas most of them, because of their embryonic lethality, showed developmental defects
Summary
Fragile sites can be defined as heritable-specific loci on human chromosomes that exhibit nonrandom gaps or breaks when chromosomes are exposed to specific cell culture conditions [1]. 0.1 Gy x 10 exposures did not increase tumorigenesis, and there was no significant difference between FHIT+/+ and FHIT−/− mice These results showed that FHIT could prevent high dose radiationinduced tumor development but has no effect in a low dose environment [32]. All FHIT heterozygous mice developed mammary tumors, whereas tumor incidence was reduced by 27% in FHIT wild type animals, which remained tumor-free at twenty months These findings (Figure 1(b)) suggested a protective role for FHIT in HER2-driven mammary tumors and point to cooperation between FHIT loss and HER2 over-expression in breast carcinogenesis [35]. Since WWOX is down-regulated in most human cancers and shows tumor suppressor function in different cell lines, Wwox knockout mice may be a useful tool to study the tumor suppressor activity of Wwox [25]. Other similar Wwox models are currently in construction as well
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