Mapping of Mcs30, a New Mammary Carcinoma Susceptibility Quantitative Trait Locus (QTL30) on Rat Chromosome 12: Identification of Fry as a Candidate Mcs Gene

被引：10

作者：

Ren, Xuefeng ^{[1
,2
,10
,11
,12
]}

Graham, Jessica C. ^{[3
,4
,5
]}

Jing, Lichen ^{[10
]}

Mikheev, Andrei M. ^{[10
]}

Gao, Yuan ^{[10
]}

Lew, Jenny Pan ^{[10
]}

Xie, Hong ^{[10
]}

Kim, Andrea S. ^{[10
]}

Shang, Xiuling ^{[1
]}

Friedman, Cynthia ^{[10
]}

Vail, Graham ^{[3
]}

Fang, Ming Zhu ^{[6
,7
]}

Bromberg, Yana ^{[8
]}

Zarbl, Helmut ^{[3
,4
,5
,6
,7
,9
,10
,11
,12
]}

机构：

[1] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA

[2] Anim Ctr, Guangdong Med Lab, Foshan, Guangdong, Peoples R China

[3] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Environm & Occupat Med, Piscataway, NJ 07103 USA

[4] Rutgers State Univ, Joint Grad Program Toxicol, Piscataway, NJ 07102 USA

[5] Univ Med & Dent New Jersey, Piscataway, NJ 07103 USA

[6] Univ Med & Dent New Jersey, NIEHS Ctr Environm Exposures & Dis, Piscataway, NJ 07103 USA

[7] Rutgers State Univ, Piscataway, NJ 07102 USA

[8] Rutgers State Univ, Dept Biochem & Microbiol, Piscataway, NJ 07102 USA

[9] Canc Inst New Jersey, New Brunswick, NJ USA

[10] FHCRC, Seattle, WA USA

[11] Univ Washington, NIEHS Ctr Ecogenet & Environm Hlth, Seattle, WA 98195 USA

[12] Univ Washington, Dept Environm & Occupat Hlth, Seattle, WA 98195 USA

来源：

PLOS ONE | 2013年 / 8卷 / 09期

关键词：

BREAST-CANCER SUSCEPTIBILITY; RADIATION HYBRID MAP; PHOSPHORYLATION SITES; NORWAY RAT; PCR ASSAY; PROTEIN; SEQUENCE; LINKAGE; GENOME; EXPRESSION;

D O I：

10.1371/journal.pone.0070930

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 similar to 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.

引用

页数：12

共 51 条

[21] Chromosomal changes associated with clinical outcome in lymph node-negative breast cancer [J].