Nuclear factor-κB activation: A molecular therapeutic target for estrogen receptor-negative and epidermal growth factor receptor family receptor-positive human breast cancer

Nuclear factor-κB (NF-κB), a transcription factor with pleotropic effects, is a downstream mediator of growth signaling in estrogen receptor (ER)-negative and erbB family particularly erbB2 (HER-2/ neu ) receptor–positive cancer. We previously reported activation of NF-κB in ER-negative breast cancer cells and breast tumor specimens, but the consequence of inhibiting NF-κB activation in this subclass of breast cancer has not been shown. In this study, we investigated the role of NF-κB activation by studying the tumorigenic potential of cells expressing genetically manipulated, inducible, dominant-negative inhibitory κB kinase (IKK) β in xenograft tumor model. Conditional inhibition of NF-κB activation by the inducible expression of dominant-negative IKKβ simultaneously blocked cell proliferation, reinstated apoptosis, and dramatically blocked xenograft tumor formation. Secondly, the humanized anti-erbB2 antibody trastuzumab (Herceptin) and the specific IKK inhibitor NF-κB essential modifier–binding domain peptide both blocked NF-κB activation and cell proliferation and reinstated apoptosis in two ER-negative and erbB2-positive human breast cancer cell lines that are used as representative model systems. Combinations of these two target-specific inhibitors synergistically blocked cell proliferation at concentrations that were singly ineffective. Inhibition of NF-κB activation with two other low molecular weight compounds, PS1145 and PS341, which inhibited IKK activity and proteasome-mediated phosphorylated inhibitory κB protein degradation, respectively, blocked erbB2-mediated cell growth and reversed antiapoptotic machinery. These results implicate NF-κB activation in the tumorigenesis and progression of ER-negative breast cancer. It is postulated that this transcription factor and its activation cascade offer therapeutic targets for erbB2-positive and ER-negative breast cancer. [Mol Cancer Ther 2007;6(7):1973–82]