NDLI: NF-κB activation in human breast cancer specimens and its role in cell proliferation and apoptosis

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NF-κB activation in human breast cancer specimens and its role in cell proliferation and apoptosis

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NF-κB activation in human breast cancer specimens and its role in cell proliferation and apoptosis

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Baily, Shanon Iglehart, J. Dirk Shi, Qian Strickland, Ian Ghosh, Sankar Biswas, Debajit K. Pardee, Arthur B.
Description	Author Affiliation: Biswas DK ( Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. debajit_biswas@dfci.harvard.edu);
Abstract	Lack of molecular targets in estrogen receptor-negative (ER-negative) breast cancer is a major therapeutic hurdle. We studied NF-kappa B activation in human breast tumors and in carcinoma cell lines. Activated NF-kappa B was detected predominantly in ER-negative vs. ER-positive breast tumors and mostly in ER-negative and ErbB2-positive tumors (86%). These in vivo results demonstrate association of activated NF-kappa B with a subgroup of human breast tumors and are consistent with previously reported in vitro observations using similar classes of human breast cancer cell lines. Finding such an association suggested functional and biological significance. Immunofluorescence demonstrated increased nuclear p65, a component of the active NF-kappa B complex, in cytokeratin 19 (CK19)-positive epithelial cells of ER-negative/ErbB2-positive tumor samples. In contrast, nuclear NF-kappa B was detected mostly in stroma of ER-negative and ErbB2-negative tumors, suggesting a role of activated NF-kappa B in intercellular signaling between epithelial and stromal cells in this type of breast cancers. To elucidate roles of activated NF-kappa B, we used an ER-negative and ErbB2-positive human breast tumor cell line (SKBr3). The polypeptide heregulin beta1 stimulated, and herceptin, the anti-ErbB2 antibody, inhibited, NF-kappa B activation in SKBr3 cells. The NF-kappa B essential modulator (NEMO)-binding domain (NBD) peptide, an established selective inhibitor of I kappa B-kinase (IKK), blocked heregulin-mediated activation of NF-kappa B and cell proliferation, and simultaneously induced apoptosis only in proliferating and not resting cells. These results substantiate the hypothesis that certain breast cancer cells rely on NF-kappa B for aberrant cell proliferation and simultaneously avoid apoptosis, thus implicating activated NF-kappa B as a therapeutic target for distinctive subclasses of ER-negative breast cancers.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	27
Volume Number	101
Language	English
Publisher	National Academy of Sciences
Publisher Date	2004-07-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Apoptosis Breast Neoplasms Pathology NF-kappa B Physiology Amino Acid Sequence Annexin A5 Metabolism Cell Cycle Cell Division Fluorescent Antibody Technique Molecular Sequence Data Neuregulin-1 Pharmacology Receptor, ErbB-2 Signal Transduction Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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