title: Integrative genomic approaches identify IKBKE as a breast cancer oncogene.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Jesse S
authors.initials: JS
authors.lastname: Boehm
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Zhao
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: So Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
authors.forename: Ian F
authors.initials: IF
authors.lastname: Dunn
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Sjostrom
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.forename: Stanislawa
authors.initials: S
authors.lastname: Weremowicz
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.forename: Carly J
authors.initials: CJ
authors.lastname: Stewart
authors.forename: Laura A
authors.initials: LA
authors.lastname: Mulvey
authors.forename: Rhine R
authors.initials: RR
authors.lastname: Shen
authors.forename: Lauren
authors.initials: L
authors.lastname: Ambrogio
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hirozane-Kishikawa
authors.forename: David E
authors.initials: DE
authors.lastname: Hill
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Grenier
authors.forename: Greg
authors.initials: G
authors.lastname: Hinkle
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Roberts
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
mesh_terms: D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D015723:Gene Library; D016678:Genome; D023281:Genomics; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051550:I-kappa B Kinase; C496565:IKBKE protein, human; D048049:Extracellular Signal-Regulated MAP Kinases