Integrative Genomic Approaches Identify IKBKE as a Breast Cancer Oncogene

Jesse S. Boehm, Jean J. Zhao, Jun Yao, So Young Kim, Ron Firestein, Ian F. Dunn, Sarah K. Sjostrom, Levi A. Garraway, Stanislawa Weremowicz, Andrea L. Richardson, Heidi Greulich, Carly J. Stewart, Laura A. Mulvey, Rhine R. Shen, Lauren Ambrogio, Tomoko Hirozane-Kishikawa, David E. Hill, Marc Vidal, Matthew Meyerson, Jennifer K. GrenierGreg Hinkle, David E. Root, Thomas M. Roberts, Eric S. Lander, Kornelia Polyak, William C. Hahn

Research output: Contribution to journalArticlepeer-review

Abstract

The karyotypic chaos exhibited by human epithelial cancers complicates efforts to identify mutations critical for malignant transformation. Here we integrate complementary genomic approaches to identify human oncogenes. We show that activation of the ERK and phosphatidylinositol 3-kinase (PI3K) signaling pathways cooperate to transform human cells. Using a library of activated kinases, we identify several kinases that replace PI3K signaling and render cells tumorigenic. Whole genome structural analyses reveal that one of these kinases, IKBKE (IKKε), is amplified and overexpressed in breast cancer cell lines and patient-derived tumors. Suppression of IKKε expression in breast cancer cell lines that harbor IKBKE amplifications induces cell death. IKKε activates the nuclear factor-kappaB (NF-κB) pathway in both cell lines and breast cancers. These observations suggest a mechanism for NF-κB activation in breast cancer, implicate the NF-κB pathway as a downstream mediator of PI3K, and provide a framework for integrated genomic approaches in oncogene discovery.

Original languageEnglish (US)
Pages (from-to)1065-1079
Number of pages15
JournalCell
Volume129
Issue number6
DOIs
StatePublished - Jun 15 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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