Mouse Normal Variation

ABSTRACT: Cancer of the prostate is influenced both by genetic predisposition and environmental factors. The identification of genes capable of modulating cancer development has the potential to unravel disease heterogeneity and aid diagnostic and prevention strategies through improved understanding of gene-environment interactions. To this end, mouse models have been developed to isolate the influences of individual genetic lesions in the context of consistent genotypes and environmental exposures. However, the extent of normal prostatic phenotypic variability dictated by a genetic background potentially capable of influencing the process of carcinogenesis has not been established. In this study we used microarray analysis to quantitate transcript abundance levels in the prostates of five commonly studied inbred mouse strains. We applied a multiclass response t-test to identify genes whose expression in each strain significantly differed from the other four strains. Approximately 13% (932 genes) exhibited significant differential expression (range 1.3 to 190-fold) in one strain relative to other strains (FDR≤10%). The pattern of variability in transcript levels did not result from variations unique to a particular strain, but rather represented genetic variability across all five strains assessed. Expression differences were confirmed by qRT-PCR, or immunohistochemistry for several genes previously shown to influence cancer progression such as Psca, Mmp7, and Clusterin. Analyses of human prostate transcripts orthologous to variable murine prostate genes identified differences in gene expression in benign epithelium that correlated with the differentiation state of adjacent tumors. For example, the expression of apolipoprotein D, a gene known to enhance resistance to cell stress in Drosophila, was expressed at significantly greater levels in benign epithelium associated with high-grade versus low-grade cancers. These data support the concept that the cellular, tissue, and organismal context contribute to oncogenesis and suggest that a predisposition to a sequence of events leading to pathology may be determined prior to cancer initiation. Keywords: mouse, prostate, transcript, variation, microarray, cancer, apolipoprotein D

ORGANISM(S): Mus musculus

PROVIDER: GSE5962 | GEO | 2007/06/01

SECONDARY ACCESSION(S): PRJNA97429

REPOSITORIES: GEO