Transcriptional networks inferred from molecular signatures of breast cancer

Ron Tongbai, Gila Idelman, Silje H. Nordgard, Wenwu Cui, Jonathan L. Jacobs, Cynthia M. Haggerty, Stephen J. Chanock, Anne Lise Børresen-Dale, Gary Livingston, Patrick Shaunessy, Chih Hung Chiang, Vessela N. Kristensen, Sven Bilke, Kevin Gardner

Research output: Contribution to journalArticlepeer-review

Abstract

Global genomic approaches in cancer research have provided new and innovative strategies for the identification of signatures that differentiate various types of human cancers. Computational analysis of the promoter composition of the genes within these signatures may provide a powerful method for deducing the regulatory transcriptional networks that mediate their collective function. In this study we have systematically analyzed the promoter composition of gene classes derived from previously established genetic signatures that recently have been shown to reliably and reproducibly distinguish five molecular subtypes of breast cancer associated with distinct clinical outcomes. Inferences made from the trends of transcription factor binding site enrichment in the promoters of these gene groups led to the identification of regulatory pathways that implicate discrete transcriptional networks associated with specific molecular subtypes of breast cancer. One of these inferred pathways predicted a role for nuclear factor-κB in a novel feed-forward, self-amplifying, autoregulatory module regulated by the ERBB family of growth factor receptors. The existence of this pathway was verified in vivo by chromatin immunoprecipitation and shown to be deregulated in breast cancer cells overexpressing ERBB2. This analysis indicates that approaches of this type can provide unique insights into the differential regulatory molecular programs associated with breast cancer and will aid in identifying specific transcriptional networks and pathways as potential targets for tumor subtype-specific therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)495-509
Number of pages15
JournalAmerican Journal of Pathology
Volume172
Issue number2
DOIs
StatePublished - Feb 2008
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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