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.

FOXO3 as a new IKK‐ε‐controlled check‐point of regulation of IFN‐β expression

“…IKK-ε was recently mapped as a new oncogene and was found to be overexpressed in prostate, ovarian, and breast cancer [20,21,36]. Interestingly, IKK-ε can replace a PI3K activity to inhibit cell-cycle arrest and apoptosis [20] processes associated with FOXO3 activity [16,37].…”

“…IKK-ε, an IKK-related kinase involved in Toll-like receptor (TLR) 3/4-mediated antiviral and antibacterial responses and key for type I IFN production [17][18][19], was recently identified as an oncogene in breast and prostate cancers [20,21]. Interestingly, its overexpression in a breast cancer model system could functionally replace PI3K constitutive activation and prevent cell-cycle arrest and apoptosis [20], processes often mediated by FOXO3 target genes, such as Cyclin D, p27/KIP1, FasL, bim [2].…”

“…Interestingly, its overexpression in a breast cancer model system could functionally replace PI3K constitutive activation and prevent cell-cycle arrest and apoptosis [20], processes often mediated by FOXO3 target genes, such as Cyclin D, p27/KIP1, FasL, bim [2].…”

“…In FOXO3-deficient mice, production of major proinflammatory cytokines IL-6 and TNF-α by dendritic cells (DCs) is increased in response to viral infection, resulting in a greater expansion of T-cell population [10]. Expression of proinflammatory cytokines as well as type I interferons (IFNs) in response to viral and microbial stimuli is regulated by a number of key transcription factors, including NF-κB and [20,21]. Interestingly, its overexpression in a breast cancer model system could functionally replace PI3K constitutive activation and prevent cell-cycle arrest and apoptosis [20], processes often mediated by FOXO3 target genes, such as Cyclin D, p27/KIP1, FasL, bim [2].…”

“…Expression of proinflammatory cytokines as well as type I interferons (IFNs) in response to viral and microbial stimuli is regulated by a number of key transcription factors, including NF-κB and [20,21]. Interestingly, its overexpression in a breast cancer model system could functionally replace PI3K constitutive activation and prevent cell-cycle arrest and apoptosis [20], processes often mediated by FOXO3 target genes, such as Cyclin D, p27/KIP1, FasL, bim [2].Based on the homology of IKK-ε and IKK-β, we hypothesized that IKK-ε may regulate FOXO3 protein activity and thereby influence the expression of cell-cycle arrest-and apoptosis-related genes. Here, we demonstrate that IKK-ε is indeed able to interact with and phosphorylate FOXO3, resulting in its inactivation and nuclear exclusion.…”