Oncogenic mutations of Ras (such as HRAS-GV12) trigger the activation of many downstream pathways, but it is likely that only a few are crucial to transformation. So, the authors assessed whether co-activation of the downstream mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways, which are often deregulated in cancer, could replace HRAS-GV12 in transformation. They created a panel of 16 immortalized human embryonic kidney cell lines (HA1E) expressing single or paired combinations of mutants activating either the MAPK (
CRAF
,
BRAF
and
MEK1
mutants) or the PI3K (PIK3CA,
AKT1
and
PTEN
mutants) pathway. The co-expression of mutants that activate AKT1 and MEK1 kinases induced anchorage-independent growth and tumour growth in immunodeficient mice, showing that the activation of specific members of the MAPK and PI3K pathways cooperate to transform human cells.
So, can kinases other than AKT1 cooperate with MEK1 to induce tumorigenesis? The authors constructed a library of 354 known and putative human kinases activated by myristoylation, introduced them into HA1E cells that expressed the MEK1 activated mutant (HA1E–M) and selected the colonies that showed anchorage-independent growth. Analysis of these cells led to the identification of five different kinases (including AKT1, a finding that validated this screening approach) that cooperated with activated MEK1 and mimicked HRAS-GV12 in inducing tumorigenesis. By analysing 179 cancer cell lines using a high-density single nucleotide polymorphism (SNP) array, they found copy-number gain and amplification of the 1q32 locus containing one of these kinase-encoding genes,
IKBKE
(inhibitor of κB kinase ε), in 8 of 49 breast cancer cell lines. Moreover, comparative genomic hybridization analysis of 30 breast tumour samples showed that 1q copy-number gain occurred in ∼33% of cases. Several strategies showed that IKBKE and its product IKKε are overexpressed in 47.6% of breast cancer samples.
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