Identifying Oncogenes

Science's STKE  19 Jun 2007:
Vol. 2007, Issue 391, pp. tw211
DOI: 10.1126/stke.3912007tw211

The extensive karyotypic abnormalities and genetic disruption characteristic of epithelial cancers make it difficult to pinpoint which mutations are critical to the development and maintenance of cancer. Boehm et al. used an integrative genomic approach to identify potential oncogenes by determining which signaling pathways downstream of oncogenic Ras contribute to cell transformation. They created 16 human embryonic kidney (HEK) cell lines that expressed single or paired combinations of mutant alleles that activated the MAPK (mitogen-activated protein kinase) or PI3K (phosphatidylinositol 3-kinase) signaling pathways and assessed their ability to recapitulate the tumorigenic phenotype of oncogenic Ras. Among these, the phenotype of a constitutively active mutant of MEK1 (a MAPK kinase) in combination with a myristoylated AKT1 mutant (myr-AKT, which constitutively activates PI3K signaling) most resembled that of oncogenic Ras. The authors then screened a library of activated kinases and identified four that could substitute for myr-AKT in eliciting an oncogenic Ras-like phenotype in combination with the MEK1 mutant. One of these, IKBKE [which encodes inhibitor of κB kinase ε (IKKε)], was amplified and overexpressed in a substantial fraction of human breast cancer cells and breast cancer cell lines. Moreover, shRNA directed against IKBKE inhibited the proliferation and survival of breast cancer cell lines with IKBKE amplification. Cells expressing constitutively active IKBKE showed an increase in NF-κB nuclear translocation and in expression of NF-κB target genes, and inhibition of NF-κB signaling increased doubling time and suppressed colony formation in IKBKE-transformed HEK cells. Furthermore, IKKε was associated with NF-κB activation in breast cancer cell lines and tissue. Thus, the authors conclude that IKBKE is a breast cancer oncogene that may link PI3K signaling to activation of the NF-κB pathway. Agami discusses the work.

J. S. Boehm, J. J. Zhao, J. Yao, S. Y. Kim, R. Firestein, I. F. Dunn, S. K. Sjostrom, L. A. Garraway, S. Weremowicz, A. L. Richardson, H. Greulich, C. J. Stewart, L. A. Mulvey, R. R. Shen, L. Ambrogio, T. Hirozane-Kishikawa, D. E. Hill, M. Vidal, M. Meyerson, J. K. Grenier, G. Hinkle, D. E. Root, T. M. Roberts, E. S. Lander, K. Polyak, W. C. Hahn, Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 129, 1065−1079 (2007). [PubMed]

R. Agami, All roads lead to ΙΚΚε. Cell 129, 1043-1045 (2007). [PubMed]