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Genomic and Proteomic Analysis Reveals a Threshold Level of MYC Required for Tumor Maintenance

¹ Division of Medical Oncology, Departments of Medicine and Pathology, ² Department of Microbiology and Immunology, ³ The Baxter Laboratory for Genetic Pharmacology, ⁴ Department of Radiology, ⁵ Department of Computer Science, ⁶ Department of Biochemistry, Howard Hughes Medical Institute, and ⁷ Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford University, Stanford, California

Requests for reprints: Dean W. Felsher, Division of Oncology, Department of Medicine, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA 94305. Phone: 650-498-5269; Fax: 650-725-1420; E-mail: dfelsher{at}stanford.edu.

Key Words: MYC-dependent tumor • regression • threshold

MYC overexpression has been implicated in the pathogenesis of most types of human cancers. MYC is likely to contribute to tumorigenesis by its effects on global gene expression. Previously, we have shown that the loss of MYC overexpression is sufficient to reverse tumorigenesis. Here, we show that there is a precise threshold level of MYC expression required for maintaining the tumor phenotype, whereupon there is a switch from a gene expression program of proliferation to a state of proliferative arrest and apoptosis. Oligonucleotide microarray analysis and quantitative PCR were used to identify changes in expression in 3,921 genes, of which 2,348 were down-regulated and 1,573 were up-regulated. Critical changes in gene expression occurred at or near the MYC threshold, including genes implicated in the regulation of the G₁-S and G₂-M cell cycle checkpoints and death receptor/apoptosis signaling. Using two-dimensional protein analysis followed by mass spectrometry, phospho-flow fluorescence-activated cell sorting, and antibody arrays, we also identified changes at the protein level that contributed to MYC-dependent tumor regression. Proteins involved in mRNA translation decreased below threshold levels of MYC. Thus, at the MYC threshold, there is a loss of its ability to maintain tumorigenesis, with associated shifts in gene and protein expression that reestablish cell cycle checkpoints, halt protein translation, and promote apoptosis. [Cancer Res 2008;68(13):5132–42]