Application of comparative functional genomics to identify best-fit mouse models to study human cancer

Abstract

Genetically modified mice have been extensively used for analyzing the molecular events that occur during tumor development. In many, if not all, cases, however, it is uncertain to what extent the mouse models reproduce features observed in the corresponding human conditions. This is due largely to lack of precise methods for direct and comprehensive comparison at the molecular level of the mouse and human tumors. Here we use global gene expression patterns of 68 hepatocellular carcinomas (HCCs) from seven different mouse models and 91 human HCCs from predefined subclasses to obtain direct comparison of the molecular features of mouse and human HCCs. Gene expression patterns in HCCs from Myc, E2f1 and Myc E2f1 transgenic mice were most similar to those of the better survival group of human HCCs, whereas the expression patterns in HCCs from Myc Tgfa transgenic mice and in diethylnitrosamine-induced mouse HCCs were most similar to those of the poorer survival group of human HCCs. Gene expression patterns in HCCs from Acox1(-/-) mice and in ciprofibrate-induced HCCs were least similar to those observed in human HCCs. We conclude that our approach can effectively identify appropriate mouse models to study human cancers.

Comparative and integrative functional genomics of HCC

“…Three recent studies provide clues on how to address the possibility that the comparison of gene expression patterns from human tumors and mouse tumors would permit the direct identification of common aberrant molecular pathways involved in tumorigenesis (Ellwood-Yen et al, 2003;Lee et al, 2004b;Sweet-Cordero et al, 2005). By comparing gene expression profiles from a prostate cancer mouse model overexpressing Myc and human prostate cancer, Figure 1 Two analytical strategies are commonly applied; supervised and unsupervised analysis.…”

“…In an effort to identify the best-fit mouse HCC models that mimic human condition, our lab has recently integrated gene expression data from human and mouse HCC (Lee et al, 2004b). Gene expression patterns of mouse HCC were obtained from seven HCC mouse models.…”

“…Third, the key regulatory elements that govern the expression patterns of gene sets reflecting clinical phenotypes are often not detectable in gene expression profile studies, because in many cases their activities are regulated at the post-transcriptional level (i.e., localization, modification and interaction with other key regulatory proteins). However, this limitation has been overcome by applying cross-comparison of multiple gene expression data sets from human HCC and animal models, uncovering evolutionarily conserved gene expression patterns during HCC progression (Lee et al, 2004b). The success of new experimental and analytical approach, comparative functional genomics, suggests that more integration of independent data sets will enhance our ability to identify key regulatory elements during HCC development.…”

“…Crossspecies comparisons of gene expression data from human cancer and mouse models indicated that gene expression signatures reflecting similar phenotypes in two species are conserved as genomic architectures including cis-regulatory elements are conserved (Ellwood-Yen et al, 2003;Lee et al, 2004b;Sweet-Cordero et al, 2005). If gene expression signatures are conserved in evolutionarily related species, it will be reasonable to speculate that the transcription factors governing these signatures would also be conserved.…”

Long-term Branched Chain Amino Acid Supplementation Ameliorates Diethylnitrosamine-induced Liver Glutathione S-transferase-p Positivity in Zucker Fatty Rats

“…Among several chemically induced, genetically modified mice, DEN-induced HCC was most similar to the expression patterns of the poor survival group of human HCCs. 8 Therefore, we treated Zucker fatty rats with DEN; and then, using this model, we estimated the effect of long-term BCAA administration, which significantly reduced the risk of HCC in cirrhotic patients with a BMI of $25. 9 The mechanism by which BCAA reduces the risk of HCC in cirrhotic patients is not clear; however, Muto et al suggested the effect of BCAA on glucose metabolism may reduce the incidence of liver cancer in cirrhotic patients with a BMI score of 25 or higher, since they may have a particularly higher incidence of hyperinsulinemia and peripheral insulin resistance.…”