title: Mapping of Mcs30, a new mammary carcinoma susceptibility quantitative trait locus (QTL30) on rat chromosome 12: identification of fry as a candidate Mcs gene.
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.
authors.affiliation: Department of Social and Preventive Medicine, the State University of New York, Buffalo, New York, United States of America ; Guangdong Medical Laboratory Animal Center, Foshan, Guangdong, China ; Fred Hutchinson Cancer Research Center (FHCRC), Seattle, Washington, United States of America ; NIEHS Center for Ecogenetics and Environmental Health, and the Department of Environmental and Occupational Health, University of Washington, Seattle, Washington, United States of America.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Ren
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Graham
authors.forename: Lichen
authors.initials: L
authors.lastname: Jing
authors.forename: Andrei M
authors.initials: AM
authors.lastname: Mikheev
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.forename: Jenny Pan
authors.initials: JP
authors.lastname: Lew
authors.forename: Hong
authors.initials: H
authors.lastname: Xie
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Kim
authors.forename: Xiuling
authors.initials: X
authors.lastname: Shang
authors.forename: Cynthia
authors.initials: C
authors.lastname: Friedman
authors.forename: Graham
authors.initials: G
authors.lastname: Vail
authors.forename: Ming Zhu
authors.initials: MZ
authors.lastname: Fang
authors.forename: Yana
authors.initials: Y
authors.lastname: Bromberg
authors.forename: Helmut
authors.initials: H
authors.lastname: Zarbl
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D040641:Quantitative Trait Loci / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D011506:Proteins
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