Publication Type | Journal Article |
Year of Publication | 2007 |
Authors | Boehm, JS, Zhao, JJ, Yao, J, Kim, SYoung, 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 |
Journal | Cell |
Volume | 129 |
Issue | 6 |
Pages | 1065-79 |
Date Published | 2007 Jun 15 |
ISSN | 0092-8674 |
Keywords | Alleles, Breast Neoplasms, Cell Line, Cell Transformation, Neoplastic, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Neoplastic, Gene Library, Genome, Genomics, Humans, I-kappa B Kinase, Models, Biological, NF-kappa B, Phosphatidylinositol 3-Kinases, Signal Transduction |
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. |
URL | http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(07)00532-6 |
DOI | 10.1016/j.cell.2007.03.052 |
Pubmed | |
Alternate Journal | Cell |
PubMed ID | 17574021 |
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 |
Cell DOI:10.1016/j.cell.2007.03.052
Integrative genomic approaches identify IKBKE as a breast cancer oncogene.
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