1. PLoS One. 2013 Sep 2;8(9):e70930. doi: 10.1371/journal.pone.0070930. eCollection
2013.
Mapping of Mcs30, a new mammary carcinoma susceptibility quantitative trait locus
(QTL30) on rat chromosome 12: identification of fry as a candidate Mcs gene.
Ren X(1), Graham JC, Jing L, Mikheev AM, Gao Y, Lew JP, Xie H, Kim AS, Shang X,
Friedman C, Vail G, Fang MZ, Bromberg Y, Zarbl H.
Author information:
(1)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.
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.
PMCID: PMC3759375
PMID: 24023717 [PubMed - indexed for MEDLINE]
PUBMED: 24023717
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