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Genetic background influences murine prostate gene expression: implications for cancer phenotypes.

Bianchi-Frias D, Pritchard C, Mecham BH, Coleman IM, Nelson PS - Genome Biol. (2007)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Fairview Avenue, Seattle, WA 98109-1024, USA.

ABSTRACT

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.

Conclusion: 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.

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Mouse prostate strain-associated gene expression and analysis in human prostate tissues: FVB/N and C57BL/6. (a) Genes differentially expressed in prostates of FVB/N and C57BL/6 strains. Heat map colors reflect fold ratio values between sample and reference pool. Columns 1-4 represent biological replicates for each strain. Rows represent individual genes. Values shown in red are relatively larger than the overall mean; values shown in green are relatively smaller than the overall mean. (b) Transcript abundance levels in benign human prostate tissues associated with high grade (7-10) or low grade (≤6) adenocarcinomas for each gene determined to be altered in mouse strain comparisons where a corresponding ortholog was identified. Genes depected in (a) and (b) are in identical order. Black box (b) and text (a) represent genes with significant differential expression in the human datasets altered in the expected orientation. Gray box (b) and text (a) represent genes with significant differential expression in the human datasets altered in the opposite orientation. (c-e) Transcript alterations for selected genes in benign tissue samples associating with high (Gleason 7-10) and low (Gleason ≤6) prostate cancers. Plots represent the 95% confidence intervals of log2 expression ratios of tissues samples relative to a cell line reference.
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Figure 5: Mouse prostate strain-associated gene expression and analysis in human prostate tissues: FVB/N and C57BL/6. (a) Genes differentially expressed in prostates of FVB/N and C57BL/6 strains. Heat map colors reflect fold ratio values between sample and reference pool. Columns 1-4 represent biological replicates for each strain. Rows represent individual genes. Values shown in red are relatively larger than the overall mean; values shown in green are relatively smaller than the overall mean. (b) Transcript abundance levels in benign human prostate tissues associated with high grade (7-10) or low grade (≤6) adenocarcinomas for each gene determined to be altered in mouse strain comparisons where a corresponding ortholog was identified. Genes depected in (a) and (b) are in identical order. Black box (b) and text (a) represent genes with significant differential expression in the human datasets altered in the expected orientation. Gray box (b) and text (a) represent genes with significant differential expression in the human datasets altered in the opposite orientation. (c-e) Transcript alterations for selected genes in benign tissue samples associating with high (Gleason 7-10) and low (Gleason ≤6) prostate cancers. Plots represent the 95% confidence intervals of log2 expression ratios of tissues samples relative to a cell line reference.

Mentions: Having established that consistent measurable differences in murine prostate gene expression occur in the context of genetic background, we next sought to determine if the orthologous genes were also variable in the human prostate, and whether the underlying normal gene expression levels, potentially representing quantitative traits, associate with aspects of human prostate carcinogenesis. We focused on transcript alterations between the C57BL/6 and FVB/N strains due to experimental evidence demonstrating that for the TRAMP model system of prostate cancer, the C57BL/6 genome delays cancer progression relative to an accelerated rate of carcinogenesis in other strains, including FVB/N [14]. We also focused on transcript differences between the C57BL/6 and BALB/c strains due to a recent report describing a reduced incidence of prostate adenocarcinomas in Pten deficient mice of a 129/C57 background relative to high rates of prostate carcinomas, up to 90% by 6 months, in Pten deficient mice of a 129/BALB/c background. These studies suggest the hypothesis that genes expressed highly in C57BL/6 prostates might function as inhibitors of carcinogenesis whereas genes expressed highly in other strains - relative to C57BL/6 - could function to promote or permit carcinogenesis. Direct comparisons of transcript abundance levels from prostates of the C57BL/6 strain against FVB/N and C57BL/6 against BALB/c identified 237 and 173 genes with significant differences, respectively (Table 1; Figures 5a and 6a).


Genetic background influences murine prostate gene expression: implications for cancer phenotypes.

Bianchi-Frias D, Pritchard C, Mecham BH, Coleman IM, Nelson PS - Genome Biol. (2007)

Mouse prostate strain-associated gene expression and analysis in human prostate tissues: FVB/N and C57BL/6. (a) Genes differentially expressed in prostates of FVB/N and C57BL/6 strains. Heat map colors reflect fold ratio values between sample and reference pool. Columns 1-4 represent biological replicates for each strain. Rows represent individual genes. Values shown in red are relatively larger than the overall mean; values shown in green are relatively smaller than the overall mean. (b) Transcript abundance levels in benign human prostate tissues associated with high grade (7-10) or low grade (≤6) adenocarcinomas for each gene determined to be altered in mouse strain comparisons where a corresponding ortholog was identified. Genes depected in (a) and (b) are in identical order. Black box (b) and text (a) represent genes with significant differential expression in the human datasets altered in the expected orientation. Gray box (b) and text (a) represent genes with significant differential expression in the human datasets altered in the opposite orientation. (c-e) Transcript alterations for selected genes in benign tissue samples associating with high (Gleason 7-10) and low (Gleason ≤6) prostate cancers. Plots represent the 95% confidence intervals of log2 expression ratios of tissues samples relative to a cell line reference.
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Related In: Results  -  Collection

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Figure 5: Mouse prostate strain-associated gene expression and analysis in human prostate tissues: FVB/N and C57BL/6. (a) Genes differentially expressed in prostates of FVB/N and C57BL/6 strains. Heat map colors reflect fold ratio values between sample and reference pool. Columns 1-4 represent biological replicates for each strain. Rows represent individual genes. Values shown in red are relatively larger than the overall mean; values shown in green are relatively smaller than the overall mean. (b) Transcript abundance levels in benign human prostate tissues associated with high grade (7-10) or low grade (≤6) adenocarcinomas for each gene determined to be altered in mouse strain comparisons where a corresponding ortholog was identified. Genes depected in (a) and (b) are in identical order. Black box (b) and text (a) represent genes with significant differential expression in the human datasets altered in the expected orientation. Gray box (b) and text (a) represent genes with significant differential expression in the human datasets altered in the opposite orientation. (c-e) Transcript alterations for selected genes in benign tissue samples associating with high (Gleason 7-10) and low (Gleason ≤6) prostate cancers. Plots represent the 95% confidence intervals of log2 expression ratios of tissues samples relative to a cell line reference.
Mentions: Having established that consistent measurable differences in murine prostate gene expression occur in the context of genetic background, we next sought to determine if the orthologous genes were also variable in the human prostate, and whether the underlying normal gene expression levels, potentially representing quantitative traits, associate with aspects of human prostate carcinogenesis. We focused on transcript alterations between the C57BL/6 and FVB/N strains due to experimental evidence demonstrating that for the TRAMP model system of prostate cancer, the C57BL/6 genome delays cancer progression relative to an accelerated rate of carcinogenesis in other strains, including FVB/N [14]. We also focused on transcript differences between the C57BL/6 and BALB/c strains due to a recent report describing a reduced incidence of prostate adenocarcinomas in Pten deficient mice of a 129/C57 background relative to high rates of prostate carcinomas, up to 90% by 6 months, in Pten deficient mice of a 129/BALB/c background. These studies suggest the hypothesis that genes expressed highly in C57BL/6 prostates might function as inhibitors of carcinogenesis whereas genes expressed highly in other strains - relative to C57BL/6 - could function to promote or permit carcinogenesis. Direct comparisons of transcript abundance levels from prostates of the C57BL/6 strain against FVB/N and C57BL/6 against BALB/c identified 237 and 173 genes with significant differences, respectively (Table 1; Figures 5a and 6a).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Fairview Avenue, Seattle, WA 98109-1024, USA.

ABSTRACT

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus