Integrative genomic approaches identify IKBKE as a breast cancer oncogene.

Published

Journal Article

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 (IKKepsilon), is amplified and overexpressed in breast cancer cell lines and patient-derived tumors. Suppression of IKKepsilon expression in breast cancer cell lines that harbor IKBKE amplifications induces cell death. IKKepsilon activates the nuclear factor-kappaB (NF-kappaB) pathway in both cell lines and breast cancers. These observations suggest a mechanism for NF-kappaB activation in breast cancer, implicate the NF-kappaB pathway as a downstream mediator of PI3K, and provide a framework for integrated genomic approaches in oncogene discovery.

Full Text

Duke Authors

Cited Authors

  • Boehm, JS; Zhao, JJ; Yao, J; Kim, SY; Firestein, R; Dunn, IF; Sjostrom, SK; Garraway, LA; Weremowicz, S; Richardson, AL; Greulich, H; Stewart, CJ; Mulvey, LA; Shen, RR; Ambrogio, L; Hirozane-Kishikawa, T; Hill, DE; Vidal, M; Meyerson, M; Grenier, JK; Hinkle, G; Root, DE; Roberts, TM; Lander, ES; Polyak, K; Hahn, WC

Published Date

  • June 15, 2007

Published In

Volume / Issue

  • 129 / 6

Start / End Page

  • 1065 - 1079

PubMed ID

  • 17574021

Pubmed Central ID

  • 17574021

International Standard Serial Number (ISSN)

  • 0092-8674

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2007.03.052

Language

  • eng

Conference Location

  • United States