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Tumor Biology |
B, Transformed Phenotype, and Survival of Breast Cancer Cells1
Departments of Biochemistry [R. R-M., G. E. S.], and Medicine [E. L. B., D. C. S.], and the Program in Research on Women’s Health [R. R-M., E. L-B., D. C. S., G. E. S.], Boston University School of Medicine, Boston, Massachusetts 02118-2394
The Her-2/neu oncogene, the second member of the epidermal growth factor (EGF) receptor family, encodes a transmembrane tyrosine kinase receptor. Overexpression of Her-2/neu in 
30% of breast cancers is associated with poor overall survival. Recently, we have found that Her-2/neu activates nuclear factor (NF)-
B via a phosphatidylinositol 3 kinase (PI3-K)-Akt kinase signaling pathway in mouse mammary tumor virus (MMTV)-Her-2/neu NF639 mouse breast cancer cells. Surprisingly, the IB kinase (IKK) kinase complex, implicated in proteasome-mediated degradation of IB-
and activation of NF-B via the canonical pathway, was not activated in these cells. Degradation of IB- was mediated via calpain, which in B cells is facilitated by phosphorylation of IB- by the protein kinase CK2. Here, we report that the inhibition of CK2 blocks Her-2/neu-mediated activation of NF-B. NF639 breast cancer cells, stably expressing CK2 or CK2' kinase-inactive mutants, displayed decreased NF-B binding and reduced ability to grow in soft agar, as well as increased sensitivity to tumor necrosis factor (TNF)- killing. Similarly, CK2 kinase-inactive subunits inhibited NF-B activity in Hs578T human breast cancer cells, which also display elevated CK2 activity. In NIH 3T3 fibroblasts, which express low basal NF-B and CK2 activities, overexpression of CK2 by retroviral gene delivery led to increased IB- turnover and the induction of classical NF-B (p50/RelA). Thus, CK2 plays an important role in Her-2/neu signaling, promoting IB- degradation and, thereby, NF-B activation. Furthermore, because ectopic CK2 activity appears sufficient to induce NF-B, the elevated CK2 activity observed in many primary human breast cancers likely plays a role in aberrant activation of NF-B and, therefore, represents a potential therapeutic target.
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