title: Identification of prostate cancer modifier pathways using parental strain expression mapping.
abstract: Inherited genetic risk factors play an important role in cancer. However, other than the Mendelian fashion cancer susceptibility genes found in familial cancer syndromes, little is known about risk modifiers that control individual susceptibility. Here we developed a strategy, parental strain expression mapping, that utilizes the homogeneity of inbred mice and genome-wide mRNA expression analyses to directly identify candidate germ-line modifier genes and pathways underlying phenotypic differences among murine strains exposed to transgenic activation of AKT1. We identified multiple candidate modifier pathways and, specifically, the glycolysis pathway as a candidate negative modulator of AKT1-induced proliferation. In keeping with the findings in the murine models, in multiple human prostate expression data set, we found that enrichment of glycolysis pathways in normal tissues was associated with decreased rates of cancer recurrence after prostatectomy. Together, these data suggest that parental strain expression mapping can directly identify germ-line modifier pathways of relevance to human disease.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Majumder
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ross
authors.forename: Yeonju
authors.initials: Y
authors.lastname: Shim
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
mesh_terms: D000818:Animals; D002455:Cell Division; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D016678:Genome; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics*; D013045:Species Specificity; D014158:Transcription, Genetic
chemical_list: D012333:RNA, Messenger