Integrative genomic approaches identify IKBKE as a breast cancer oncogene.

Cell
Authors
Keywords
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 (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.

Year of Publication
2007
Journal
Cell
Volume
129
Issue
6
Pages
1065-79
Date Published
2007 Jun 15
ISSN
0092-8674
URL
DOI
10.1016/j.cell.2007.03.052
PubMed ID
17574021
Links
Grant list
CA015607 / CA / NCI NIH HHS / United States
R01 CA094074-01A1 / CA / NCI NIH HHS / United States
CA30002 / CA / NCI NIH HHS / United States
P50 CA089393-080014 / CA / NCI NIH HHS / United States
CA89021 / CA / NCI NIH HHS / United States
P50 CA089393 / CA / NCI NIH HHS / United States
R01 CA094074-05 / CA / NCI NIH HHS / United States
P50 CA089393-070014 / CA / NCI NIH HHS / United States
R01 CA094074-02 / CA / NCI NIH HHS / United States
P50 CA089393-060014 / CA / NCI NIH HHS / United States
R01 CA094074-04 / CA / NCI NIH HHS / United States
R01 CA094074-03 / CA / NCI NIH HHS / United States
P50 CA112962 / CA / NCI NIH HHS / United States
R01 CA094074 / CA / NCI NIH HHS / United States
K01 CA94223 / CA / NCI NIH HHS / United States