Genetic background influences murine prostate gene expression: implications for cancer phenotypes.
BACKGROUND
Cancer of the prostate is influenced by both 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. 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 normal prostatic phenotypic variability dictated by a genetic background that is potentially capable of influencing the process of carcinogenesis has not been established.


RESULTS
In this study we used microarray analysis to quantify transcript levels in the prostates of five commonly studied inbred mouse strains. We applied a multiclass response t-test and determined that approximately 13% (932 genes) exhibited differential expression (range 1.3-190-fold) in any one strain relative to other strains (false discovery rate < or = 10%). Expression differences were confirmed by quantitative RT-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 gene encoding apolipoprotein D, which is known to enhance resistance to cell stress, was expressed at significantly greater levels in benign epithelium associated with high-grade versus low-grade cancers.


CONCLUSIONS
These studies 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 exist prior to cancer initiation.
Bianchi-Frias
Daniella
D
Division of Human Biology, Fred Hutchinson Cancer Research Center, Fairview Avenue, Seattle, WA 98109-1024, USA.
Pritchard
Colin
C
Mecham
Brigham H
BH
Coleman
Ilsa M
IM
Nelson
Peter S
PS
D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics*; D013045:Species Specificity