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Research Articles

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

Departments of ¹ Cancer Biology and ² Medical Oncology, Dana-Farber Cancer Institute; ³ Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts and ⁴ Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut

Requests for reprints: Debajit K. Biswas, Department of Cancer Biology, Dana-Farber Cancer Institute, Smith Room 1058, 44 Binney Street, Boston, MA 02115. Phone: 617-632-4684; Fax: 617-632-3709. E-mail: Debajit_Biswas{at}dfci.harvard.edu

Abstract

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

Grant support: Department of Defense Center of Excellence grant DAMD 17-02-1-0692, National Cancer Institute Specialized Program of Research Excellence grant in Breast Cancer at Harvard, and Research Funds of Friends of Dana-Farber Cancer Institute.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: S. Singh and Q. Shi contributed equally to this work.

⁵ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 2/ 6/07; revised 4/18/07; accepted 5/25/07.