期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：27
页码：10137-10142
DOI：10.1073/pnas.0403621101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 {beta}1 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.
