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) 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.
Boehm
Jesse S
JS
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Zhao
Jean J
JJ
Yao
Jun
J
Kim
So Young
SY
Firestein
Ron
R
Dunn
Ian F
IF
Sjostrom
Sarah K
SK
Garraway
Levi A
LA
Weremowicz
Stanislawa
S
Richardson
Andrea L
AL
Greulich
Heidi
H
Stewart
Carly J
CJ
Mulvey
Laura A
LA
Shen
Rhine R
RR
Ambrogio
Lauren
L
Hirozane-Kishikawa
Tomoko
T
Hill
David E
DE
Vidal
Marc
M
Meyerson
Matthew
M
Grenier
Jennifer K
JK
Hinkle
Greg
G
Root
David E
DE
Roberts
Thomas M
TM
Lander
Eric S
ES
Polyak
Kornelia
K
Hahn
William C
WC
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
D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051550:I-kappa B Kinase; C496565:IKBKE protein, human; D048049:Extracellular Signal-Regulated MAP Kinases