Fhit-flox Mouse

Fhit, the product of the fragile histidine triad (FHIT) gene, is an enzyme that hydrolyzes the dinucleotide Ap3A. The FHIT gene encloses the common chromosomal fragile site FRA3B and is associated with genomic instability, apoptosis, and DNA damage [1,2]. It has been hypothesized to act as a tumor suppressor gene, playing crucial roles in cancer-related biological processes [1].

Fhit knockout mice are predisposed to tumor development [4]. In breast cancer, when one Fhit allele was inactivated (Fhit(+/-)) in mice crossed with FVB/N mice carrying the rat HER2/neu proto-oncogene, all Fhit heterozygous mice developed mammary tumors, while 27% of mice with both Fhit alleles (Fhit(+/+)) remained tumor-free at twenty months, suggesting a protective role for FHIT in HER2-driven mammary tumors [5]. Also, loss of Fhit in cells leads to nucleotide imbalance, spontaneous replication stress, and DNA breaks, as Fhit increases thymidine kinase 1 (TK1) translation to balance deoxyribonucleotide triphosphates (dNTPs) for efficient DNA replication [3].

In conclusion, Fhit is a key factor in maintaining genome stability and has a significant tumor-suppressing role. Mouse models, especially Fhit knockout mice, have been instrumental in revealing its function in tumor development, particularly in breast cancer. Understanding Fhit's function provides insights into cancer biology and may potentially lead to new therapeutic strategies.