Tax activates NF-κB through direct interactions with the IKK complex (12) and that activation of NF-κB is required for transformation of rat fibroblasts by Tax (13). Other viral transforming proteins, such as the Epstein-Barr virus–encoded (EBV-encoded) proteins, EBV protein nuclear antigen 2, the latent membrane protein 1 (LMP-1), the Simian virus-40–encoded Large-T, and adenovirus-encoded E1A, all stimulate NF-κB transcriptional activity (14). Consistent with a role for this pathway in transformation and tumorigenesis, many human solid tumor cell lines display increased nuclear NF-κB levels and/or increased NF-κB–dependent reporter expression.

Further support for the involvement of NF-κB in oncogenesis comes from experiments in which the NF-κB pathway has been directly perturbed. Inhibition of NF-κB by expression of a modified form of IκBα (superrepressor IκBα)(15) or by a dominant negative form of IKK (16) blocks focus formation induced by Ras. Tumorigenesis driven by the oncogenic fusion protein BCR-ABL, which activates NF-κB, is also blocked by super-repressor IκBα (17). NF-κB is activated in Hodgkin’s lymphoma (18)(and in a variety of transformed cell lines), and inhibition of NF-κB blocks growth of these lymphoma cells (18). Van Waes and colleagues (19) recently blocked NF-κB function in head and neck squamous cell carcinoma cells and showed that this inhibited xenograftderived tumor growth. Sovak et al.(20) reported that the classic form of NF-κB (p50-p65) is localized to the nucleus in breast cancer cell lines and in some breast tumors (20). Our observations agree that NF-κB appears to be dysregulated in breast cancer, but we find that human breast tumors display an accumulation of nuclear p52 and Bcl-3 along with c-Rel, rather than consistent activation of p65 (21). Presumably Bcl-3 promotes transcriptional activity through interactions with p52.