In the pursuit of complexity: systems medicine in cancer biology.

Adler et al., in a paper appearing in Nature Genetics, exploited the intersect of genetic information from expression profiles with that from array comparative genomic hybridization in human breast cancers to identify genes that may induce the transcription of the prognostic "wound response" expression signature. The amplification of two genes, MYC and CSN5, appeared to be correlated with the wound response cassette. In vitro validation showed that the wound signature could be induced in MCF10A cells only when MYC and CSN5 were coexpressed. This work shows that the intersect analysis of gene amplification and transcriptional expression on a genome-wide scale can uncover complex conditional interactions embedded in the systems map of transcriptional regulation.

[1]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Anna V. Ivshina,et al.  Syndrome approach for computer recognition of fuzzy systems and its application to immunological diagnostics and prognosis of human cancer , 1996 .

[3]  Jeffrey T. Chang,et al.  Oncogenic pathway signatures in human cancers as a guide to targeted therapies , 2006, Nature.

[4]  Howard Y. Chang,et al.  Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[5]  E. Liu,et al.  Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[6]  W. Kaelin The Concept of Synthetic Lethality in the Context of Anticancer Therapy , 2005, Nature Reviews Cancer.

[7]  Z. Weng,et al.  A Global Map of p53 Transcription-Factor Binding Sites in the Human Genome , 2006, Cell.

[8]  Howard Y. Chang,et al.  Genetic regulators of large-scale transcriptional signatures in cancer , 2006, Nature Genetics.

[9]  P. Hall,et al.  An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[10]  D. Botstein,et al.  The transcriptional program in the response of human fibroblasts to serum. , 1999, Science.

[11]  Rafael A Irizarry,et al.  Global synthetic-lethality analysis and yeast functional profiling. , 2006, Trends in genetics : TIG.

[12]  J. Mesirov,et al.  An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis , 2005, Nature Genetics.

[13]  R. Tibshirani,et al.  Diagnosis of multiple cancer types by shrunken centroids of gene expression , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[14]  T. Golub,et al.  Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma , 2005, Nature.

[15]  Lance D. Miller,et al.  Identifying gene expression changes in breast cancer that distinguish early and late relapse among uncured patients , 2006, Bioinform..

[16]  T. Golub,et al.  A Mechanism of Cyclin D1 Action Encoded in the Patterns of Gene Expression in Human Cancer , 2003, Cell.

[17]  E. Liu,et al.  Pharmacologic modulation of glycogen synthase kinase-3beta promotes p53-dependent apoptosis through a direct Bax-mediated mitochondrial pathway in colorectal cancer cells. , 2005, Cancer research.