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Abstract
Rat strains differ dramatically in their susceptibility to mammary carcinogenesis. On the assumption that susceptibility genes are conserved across mammalian species and hence inform human carcinogenesis, numerous investigators have used genetic linkage studies in rats to identify genes responsible for differential susceptibility to carcinogenesis. Using a genetic backcross between the resistant Copenhagen (Cop) and susceptible Fischer 344 (F344) strains, we mapped a novel mammary carcinoma susceptibility (Mcs30) locus to the centromeric region on chromosome 12 (LOD score of ∼8.6 at the D12Rat59 marker). The Mcs30 locus comprises approximately 12 Mbp on the long arm of rat RNO12 whose synteny is conserved on human chromosome 13q12 to 13q13. After analyzing numerous genes comprising this locus, we identified Fry, the rat ortholog of the furry gene of Drosophila melanogaster, as a candidate Mcs gene. We cloned and determined the complete nucleotide sequence of the 13 kbp Fry mRNA. Sequence analysis indicated that the Fry gene was highly conserved across evolution, with 90% similarity of the predicted amino acid sequence among eutherian mammals. Comparison of the Fry sequence in the Cop and F344 strains identified two non-synonymous single nucleotide polymorphisms (SNPs), one of which creates a putative, de novo phosphorylation site. Further analysis showed that the expression of the Fry gene is reduced in a majority of rat mammary tumors. Our results also suggested that FRY activity was reduced in human breast carcinoma cell lines as a result of reduced levels or mutation. This study is the first to identify the Fry gene as a candidate Mcs gene. Our data suggest that the SNPs within the Fry gene contribute to the genetic susceptibility of the F344 rat strain to mammary carcinogenesis. These results provide the foundation for analyzing the role of the human FRY gene in cancer susceptibility and progression.
Highlights
Breast cancer remains the most prevalent cancer among US women, with an estimated 226,870 new cases and 39,510 deaths occurring in 2012 (National Cancer Institute SEER CancerStatistics)
Genome-wide Screen for mammary carcinoma susceptibility (Mcs) (QTL) Loci We performed linkage analysis using a genetic backcross between two rat strains with differential susceptibility to NMUinduced mammary carcinomas
This new susceptibility locus on RNO12 was designated as Mcs30 (QTL30) and was assigned the RGD ID: 7243862
Summary
A multitude of genetic alterations and molecular pathways have been implicated in the pathogenesis of breast cancer [1,2], there remain significant gaps in knowledge regarding the biology and etiology, in particular, genetic susceptibility to this disease. Rat strains vary widely in their genetic susceptibility to mammary carcinogenesis. On the assumption that tumor suppressors are conserved across mammalian species, investigators have carried out numerous genetic linkage studies in rats to identify genes responsible for this differential susceptibility [3,4,5,6,7,8,9,10]. Prior studies in rats identified 29 strain-specific mammary carcinoma susceptibility (Mcs) loci [11,12]. Identification and functional characterization of additional Mcs genes will enhance our understanding of the genetic basis for the differential susceptibility to mammary carcinogenesis
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