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Roles of ikB-alpha Protein Kinases in Activation of NF-kB in Breast Cancer

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Aberrant activation of NF-kappaB transcription factors has been implicated in the pathogenesis of breast cancer. We previously demonstrated elevated activity of IKKalpha, IKKBeta and protein kinase CK2 in primary human breast cancer specimens and in cultured cells. A novel inducible IKK protein termed IKK-iIKKepsilon has been characterized as a potential NF-kappaB activator. Here we provide evidence that implicates IKK-iIKKepsilon in the pathogenesis of breast cancer. We demonstrate IKK-iIKKepsilon expression in primary human breast cancer specimens and carcinogen-induced mouse mammary tumors. Multiple breast cancer cell lines showed higher levels of IKK-iIKKepsilon and kinase activity compared to untransformed MCF-10F breast epithelial cells. Interestingly, IKK-iIKKepsilon expression correlated with CK2alpha expression in mammary glands and breast tumors derived from MMTV-CK2alpha transgenic mice. Ectopic CK2 expression in untransformed cells led to increased IKK-iIKKepsilon mRNA and protein levels. Inhibition of CK2alpha via the pharmacological inhibitor apigenin or upon transfection of a CK2 kinase inactive subunit reduced IKK-iIKKepsilon levels. Expression of a kinase inactive IKK-iIKK mutant in breast cancer cells reduced NF-kappaB activity as judged by transfection assays of reporters driven either by NF-kappaB elements or the promoters of two NF-kappaB target genes, cyclin D1 and re1B. Importantly, the kinase inactive IKK-iIKKepsilon mutant reduced the endogenous levels of these genes as well as the ability of breast cancer cells to grow in soft agar or form invasive colonies in matrigel. Thus, CK2 induces functional IKK-iIKKepsilon, which is an important mediator of the activation of NF-kappaB that plays a critical role in the pathogenesis of breast cancer.

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  • Biochemistry
  • Medicine and Medical Research

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