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A core MYC gene expression signature is prominent in basal-like breast cancer but only partially overlaps the core serum response.

Chandriani S, Frengen E, Cowling VH, Pendergrass SA, Perou CM, Whitfield ML, Cole MD - PLoS ONE (2009)

Bottom Line: 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.The 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ, USA.

ABSTRACT

Background: The MYC oncogene contributes to induction and growth of many cancers but the full spectrum of the MYC transcriptional response remains unclear.

Methodology/principal findings: Using microarrays, we conducted a detailed kinetic study of genes that respond to MYCN or MYCNDeltaMBII induction in primary human fibroblasts. In parallel, we determined the response to steady state overexpression of MYCN and MYCNDeltaMBII 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/significance: The 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.

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Related in: MedlinePlus

Serum stimulation vs. MYC overexpression.A. The expression profiling data for serum responsive study [20] and this study were linked. The data corresponding to the (CSR) gene list were extracted from the linked dataset. The data for these genes were hierarchically clustered in one dimension (genes). Upon serum stimulation, samples were harvested from 0 hrs to 36 hrs. B. The same procedure was performed starting with the Core MYC signature gene list. The data for each of the Core MYC signature genes was extracted from the linked dataset and clustered in one dimension.
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pone-0006693-g004: Serum stimulation vs. MYC overexpression.A. The expression profiling data for serum responsive study [20] and this study were linked. The data corresponding to the (CSR) gene list were extracted from the linked dataset. The data for these genes were hierarchically clustered in one dimension (genes). Upon serum stimulation, samples were harvested from 0 hrs to 36 hrs. B. The same procedure was performed starting with the Core MYC signature gene list. The data for each of the Core MYC signature genes was extracted from the linked dataset and clustered in one dimension.

Mentions: The c-MYC gene was the first oncogene shown to be part of the immediate early response to serum stimulation [16]. Therefore, it was of interest to compare the response of fibroblasts to MYCN overexpression with their response to serum. We utilized a publicly available serum stimulation gene expression dataset of normal human fibroblasts, and a list of genes determined to represent the “Core Serum Response” (CSR) [20]. A priori, we expected that MYCN overexpression might induce a gene expression response that was similar to the serum response. Specifically, we thought that MYCN would induce genes that are called delayed early response genes. Delayed early response genes are defined as those that are dependent on the initial induction of a transcriptional regulator or signaling pathway. This initial transcriptional response subsequently induces a secondary set of genes that are not induced by the primary signal. These expectations were met for a fraction of the CSR genes that could be mapped to our array platform (Figure 4A). A set of genes (80 out of 354; 23%) is induced both by MYCN and by serum, and the kinetics of induction in the CSR are consistent with these genes being downstream of MYC. In the serum induced gene profiles, the c-MYC gene itself is induced at 2–4 hr, similar to the response described in numerous studies. However, in the MYCN-ER and steady state overexpression profiles, the c-MYC gene itself scores as repressed due to autoregulation. It is important to add that although there is an overlap between the CSR and MYCN induction, many of the CSR genes would not have passed the threshold as MYC targets in either the kinetic or steady state experiments. Not surprisingly, many CSR genes are not MYCN responsive, implying that these genes are regulated by MYC independent pathways or require some combinatorial signal.


A core MYC gene expression signature is prominent in basal-like breast cancer but only partially overlaps the core serum response.

Chandriani S, Frengen E, Cowling VH, Pendergrass SA, Perou CM, Whitfield ML, Cole MD - PLoS ONE (2009)

Serum stimulation vs. MYC overexpression.A. The expression profiling data for serum responsive study [20] and this study were linked. The data corresponding to the (CSR) gene list were extracted from the linked dataset. The data for these genes were hierarchically clustered in one dimension (genes). Upon serum stimulation, samples were harvested from 0 hrs to 36 hrs. B. The same procedure was performed starting with the Core MYC signature gene list. The data for each of the Core MYC signature genes was extracted from the linked dataset and clustered in one dimension.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2723908&req=5

pone-0006693-g004: Serum stimulation vs. MYC overexpression.A. The expression profiling data for serum responsive study [20] and this study were linked. The data corresponding to the (CSR) gene list were extracted from the linked dataset. The data for these genes were hierarchically clustered in one dimension (genes). Upon serum stimulation, samples were harvested from 0 hrs to 36 hrs. B. The same procedure was performed starting with the Core MYC signature gene list. The data for each of the Core MYC signature genes was extracted from the linked dataset and clustered in one dimension.
Mentions: The c-MYC gene was the first oncogene shown to be part of the immediate early response to serum stimulation [16]. Therefore, it was of interest to compare the response of fibroblasts to MYCN overexpression with their response to serum. We utilized a publicly available serum stimulation gene expression dataset of normal human fibroblasts, and a list of genes determined to represent the “Core Serum Response” (CSR) [20]. A priori, we expected that MYCN overexpression might induce a gene expression response that was similar to the serum response. Specifically, we thought that MYCN would induce genes that are called delayed early response genes. Delayed early response genes are defined as those that are dependent on the initial induction of a transcriptional regulator or signaling pathway. This initial transcriptional response subsequently induces a secondary set of genes that are not induced by the primary signal. These expectations were met for a fraction of the CSR genes that could be mapped to our array platform (Figure 4A). A set of genes (80 out of 354; 23%) is induced both by MYCN and by serum, and the kinetics of induction in the CSR are consistent with these genes being downstream of MYC. In the serum induced gene profiles, the c-MYC gene itself is induced at 2–4 hr, similar to the response described in numerous studies. However, in the MYCN-ER and steady state overexpression profiles, the c-MYC gene itself scores as repressed due to autoregulation. It is important to add that although there is an overlap between the CSR and MYCN induction, many of the CSR genes would not have passed the threshold as MYC targets in either the kinetic or steady state experiments. Not surprisingly, many CSR genes are not MYCN responsive, implying that these genes are regulated by MYC independent pathways or require some combinatorial signal.

Bottom Line: 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.The 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ, USA.

ABSTRACT

Background: The MYC oncogene contributes to induction and growth of many cancers but the full spectrum of the MYC transcriptional response remains unclear.

Methodology/principal findings: Using microarrays, we conducted a detailed kinetic study of genes that respond to MYCN or MYCNDeltaMBII induction in primary human fibroblasts. In parallel, we determined the response to steady state overexpression of MYCN and MYCNDeltaMBII 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/significance: The 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.

Show MeSH
Related in: MedlinePlus