Herceptin Research Today is a free monthly online journal that collates and summarizes the latest research about Herceptin, including details on side-effects, breast cancer, treatment, therapy.

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

Singh S, Shi Q, Bailey ST, Palczewski MJ, Pardee AB, Iglehart JD, Biswas DK

Department of Cancer Biology, Dana-Farber Cancer Institute, Smith Room 1058, 44 Binney Street, Boston, MA 02115, USA.

Nuclear factor-kappaB (NF-kappaB), 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-kappaB in ER-negative breast cancer cells and breast tumor specimens, but the consequence of inhibiting NF-kappaB activation in this subclass of breast cancer has not been shown. In this study, we investigated the role of NF-kappaB activation by studying the tumorigenic potential of cells expressing genetically manipulated, inducible, dominant-negative inhibitory kappaB kinase (IKK) beta in xenograft tumor model. Conditional inhibition of NF-kappaB activation by the inducible expression of dominant-negative IKKbeta 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-kappaB essential modifier-binding domain peptide both blocked NF-kappaB 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-kappaB activation with two other low molecular weight compounds, PS1145 and PS341, which inhibited IKK activity and proteasome-mediated phosphorylated inhibitory kappaB protein degradation, respectively, blocked erbB2-mediated cell growth and reversed antiapoptotic machinery. These results implicate NF-kappaB 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.

Published 10 July 2007 in Mol Cancer Ther, 6(7): 1973-82.
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