@article{ff0f7fb7960d49ebb0dcf0785b6f0418,
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 (IKKε), is amplified and overexpressed in breast cancer cell lines and patient-derived tumors. Suppression of IKKε expression in breast cancer cell lines that harbor IKBKE amplifications induces cell death. IKKε 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.",
author = "Boehm, {Jesse S.} and Zhao, {Jean J.} and Jun Yao and Kim, {So Young} and Ron Firestein and Dunn, {Ian F.} and Sjostrom, {Sarah K.} and Garraway, {Levi A.} and Stanislawa Weremowicz and Richardson, {Andrea L.} and Heidi Greulich and Stewart, {Carly J.} and Mulvey, {Laura A.} and Shen, {Rhine R.} and Lauren Ambrogio and Tomoko Hirozane-Kishikawa and Hill, {David E.} and Marc Vidal and Matthew Meyerson and Grenier, {Jennifer K.} and Greg Hinkle and Root, {David E.} and Roberts, {Thomas M.} and Lander, {Eric S.} and Kornelia Polyak and Hahn, {William C.}",
note = "Funding Information: We thank D. Sabatini, N. Hacohen, and T. Golub for advice. We thank E. Shin for assistance with IHC, L. Prickett for assistance with fluorescence-activated cell sorting, and H. Widlund for reagents and helpful discussions. We thank E. Knipp and J.T. Boehm for assistance in manuscript preparation and members of the Hahn laboratory for helpful discussions and support. This work was supported in part by grants K01 CA94223 (W.C.H.), P50 CA112962 (W.C.H.), CA30002 (T.R.), CA89021 (T.R.), CA015607 (T.R.) from the NIH, the Tisch Family Fund (W.C.H. and K.P.), DFCI High Tech Fund (S. Korsmeyer), the DFCI Strategic Planning Initiative for support (W.H. and M.V.), an Ellison Foundation grant (M.V.), a Breast Cancer Center of Excellence Award (DAMD170210692, K.P.), a Claudia Barr Award (J.J.Z.), a Woman's Cancer Program Award (J.J.Z.), and a Department of Defense Breast Cancer Program Award BC051565 (J.J.Z.). In compliance with Harvard Medical School guidelines, we disclose that W.C.H., T.M.R., M.M., and K.P. are consultants for Novartis Pharmaceuticals, Inc. ",
year = "2007",
month = jun,
day = "15",
doi = "10.1016/j.cell.2007.03.052",
language = "English (US)",
volume = "129",
pages = "1065--1079",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",
}