Integrated cross-species transcriptional network analysis of metastatic susceptibility.
Metastatic disease is the proximal cause of mortality for most cancers and remains a significant problem for the clinical management of neoplastic disease. Recent advances in global transcriptional analysis have enabled better prediction of individuals likely to progress to metastatic disease. However, minimal overlap between predictive signatures has precluded easy identification of key biological processes contributing to the prometastatic transcriptional state. To overcome this limitation, we have applied network analysis to two independent human breast cancer datasets and three different mouse populations developed for quantitative analysis of metastasis. Analysis of these datasets revealed that the gene membership of the networks is highly conserved within and between species, and that these networks predicted distant metastasis free survival. Furthermore these results suggest that susceptibility to metastatic disease is cell-autonomous in estrogen receptor-positive tumors and associated with the mitotic spindle checkpoint. In contrast, nontumor genetics and pathway activities-associated stromal biology are significant modifiers of the rate of metastatic spread of estrogen receptor-negative tumors. These results suggest that the application of network analysis across species may provide a robust method to identify key biological programs associated with human cancer progression.
Laboratory of Population Genetics, and Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Insitute, National Institutes of Health, Bethesda, MD 20892, USA.
Ying
Y
Hu
Gang
G
Wu
Michael
M
Rusch
Luanne
L
Lukes
Kenneth H
KH
Buetow
Jinghui
J
Zhang
Kent W
KW
Hunter
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D030541:Databases, Genetic; D018450:Disease Progression; D004198:Disease Susceptibility; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013045:Species Specificity; D060265:Tetraspanin 25 / Q000378:metabolism
D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; C122167:TPX2 protein, human; D060265:Tetraspanin 25