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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 …