Genetic regulators of large-scale transcriptional signatures in cancer

Abstract

Gene expression signatures encompassing dozens to hundreds of genes have been associated with many important parameters of cancer, but mechanisms of their control are largely unknown. Here we present a method based on genetic linkage that can prospectively identify functional regulators driving large-scale transcriptional signatures in cancer. Using this method we show that the wound response signature, a poor-prognosis expression pattern of 512 genes in breast cancer, is induced by coordinate amplifications of MYC and CSN5 (also known as JAB1 or COPS5). This information enabled experimental recapitulation, functional assessment and mechanistic elucidation of the wound signature in breast epithelial cells.

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Figure 1: Overview of SLAMS analysis procedure.
Figure 2: Linkage of MYC and CSN5 amplifications with wound signature.
Figure 3: Association of MYC and CSN5 genomic DNA amplification with wound signature in an independent set of breast tumors.
Figure 4: MYC and CSN5 activate the wound signature.
Figure 5: MYC and CSN5 induce features of invasive cancer cells.
Figure 6: CSN5 induces MYC ubiquitination, turnover and activation of select MYC target genes.
Figure 7: CSN5 is required for SKP2 activity, stability and transcriptional activity of MYC.

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Acknowledgements

We thank E. Huntziker, A.E. Oro, W. Tansey, L. Bemis, X. Chen and D.W. Felsher for reagents, T.W. Ridky and P.A. Khavari for assistance with animal experiments, Y. Liu for technical assistance, members of the Program in Epithelial Biology for discussion and D.W. Felsher, P.A. Khavari, A.E. Oro, E. Segal and J.L. Rinn for comments on the manuscript. This work was supported by grants from the US National Institutes of Health (AR050007, CA09302) and the Dutch Cancer Society (NKB 2002-2575). H.Y.C. is a Damon Runyon Scholar supported by the Damon Runyon Cancer Research Foundation.

Author information

Correspondence to Howard Y Chang.

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Competing interests

A.S.A., M.L. and H.Y.C. are named as inventors on a patent application describing the SLAMS method.

Supplementary information

Supplementary Fig. 1

DNA copy number and expession patterns of MYC and CSN5. (PDF 66 kb)

Supplementary Fig. 2

Nonlinear relationship between wound signature score and probability of gene coregulation. (PDF 75 kb)

Supplementary Table 1

DNA amplification associated with wound signature expression. (PDF 259 kb)

Supplementary Table 2

List of published prognostic signatures in human breast cancer used in the gene module map analysis. (PDF 217 kb)

Supplementary Table 3

MYC target genes that are coactivated by CSN5 expression. (PDF 240 kb)

Supplementary Table 4

Primer sequences for quantitative microsatellite analysis (QuMA). (PDF 154 kb)

Supplementary Note (PDF 120 kb)

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Adler, A., Lin, M., Horlings, H. et al. Genetic regulators of large-scale transcriptional signatures in cancer. Nat Genet 38, 421–430 (2006). https://doi.org/10.1038/ng1752

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