Integrative Genomic Approaches Identify IKBKE as a Breast Cancer Oncogene

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) sign...

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Bibliographic Details
Published in:	Cell Vol. 129; no. 6; pp. 1065 - 1079
Main Authors:	Boehm, Jesse S., Zhao, Jean J., Yao, Jun, Kim, So Young, Firestein, Ron, Dunn, Ian F., Sjostrom, Sarah K., Garraway, Levi A., Weremowicz, Stanislawa, Richardson, Andrea L., Greulich, Heidi, Stewart, Carly J., Mulvey, Laura A., Shen, Rhine R., Ambrogio, Lauren, Hirozane-Kishikawa, Tomoko, Hill, David E., Vidal, Marc, Meyerson, Matthew, Grenier, Jennifer K., Hinkle, Greg, Root, David E., Roberts, Thomas M., Lander, Eric S., Polyak, Kornelia, Hahn, William C.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 15-06-2007
Subjects:	Alleles Breast Neoplasms - genetics Breast Neoplasms - metabolism Cell Line Cell Transformation, Neoplastic Extracellular Signal-Regulated MAP Kinases - metabolism Gene Expression Regulation, Neoplastic Gene Library Genome Genomics Humans I-kappa B Kinase - genetics Models, Biological NF-kappa B - metabolism Phosphatidylinositol 3-Kinases - metabolism Signal Transduction
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Summary:	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 (IKKɛ), is amplified and overexpressed in breast cancer cell lines and patient-derived tumors. Suppression of IKKɛ expression in breast cancer cell lines that harbor IKBKE amplifications induces cell death. IKKɛ 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0092-8674 1097-4172
DOI:	10.1016/j.cell.2007.03.052