Abstract
BackgroundThe MYC oncogene contributes to induction and growth of many cancers but the full spectrum of the MYC transcriptional response remains unclear.Methodology/Principal FindingsUsing microarrays, we conducted a detailed kinetic study of genes that respond to MYCN or MYCNΔMBII induction in primary human fibroblasts. In parallel, we determined the response to steady state overexpression of MYCN and MYCNΔMBII in the same cell type. An overlapping set of 398 genes from the two protocols was designated a ‘Core MYC Signature’ and used for further analysis. Comparison of the Core MYC Signature to a published study of the genes induced by serum stimulation revealed that only 7.4% of the Core MYC Signature genes are in the Core Serum Response and display similar expression changes to both MYC and serum. Furthermore, more than 50% of the Core MYC Signature genes were not influenced by serum stimulation. In contrast, comparison to a panel of breast cancers revealed a strong concordance in gene expression between the Core MYC Signature and the basal-like breast tumor subtype, which is a subtype with poor prognosis. This concordance was supported by the higher average level of MYC expression in the same tumor samples.Conclusions/SignificanceThe Core MYC Signature has clinical relevance as this profile can be used to deduce an underlying genetic program that is likely to contribute to a clinical phenotype. Therefore, the presence of the Core MYC Signature may predict clinical responsiveness to therapeutics that are designed to disrupt MYC-mediated phenotypes.
Highlights
The MYC proto-oncogene is an essential gene whose function is required for normal mouse and fly development [1,2,3]
This approach allowed us to isolate the transcriptional response to MYC in a controlled system and to show that the core MYC signature is present in a gene expression data set of breast cancer samples, which identifies the basal subtype of breast cancer and may indicate one of the genetic determinants of this group
Experimental design The pathology that results from MYC overexpression is the consequence of altered expression of both direct and indirect target genes
Summary
The MYC proto-oncogene is an essential gene whose function is required for normal mouse and fly development [1,2,3]. Motivated by the observation that wound healing and tumor growth share many common physiological characteristics (review, [19]), Chang and colleagues showed that the expression of the serum response in cancer cells is a predicator of cancer patient survival and metastasis [20]. They propose a model in which the wound signature in breast cancer is induced by the coordinate amplification of MYC and CSN5, a component of a ubiquitin ligase complex [21]. This approach allowed us to isolate the transcriptional response to MYC in a controlled system and to show that the core MYC signature is present in a gene expression data set of breast cancer samples, which identifies the basal subtype of breast cancer and may indicate one of the genetic determinants of this group
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