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

Lack of molecular targets in estrogen receptor-negative (ER-negative) breast cancer is a major therapeutic hurdle. We studied NF-kappaB activation in human breast tumors and in carcinoma cell lines. Activated NF-kappaB 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-kappaB 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-kappaB complex, in cytokeratin 19 (CK19)-positive epithelial cells of ER-negative/ErbB2-positive tumor samples. In contrast, nuclear NF-kappaB was detected mostly in stroma of ER-negative and ErbB2-negative tumors, suggesting a role of activated NF-kappaB in intercellular signaling between epithelial and stromal cells in this type of breast cancers. To elucidate roles of activated NF-kappaB, 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-kappaB activation in SKBr3 cells. The NF-kappaB essential modulator (NEMO)-binding domain (NBD) peptide, an established selective inhibitor of IkappaB-kinase (IKK), blocked heregulin-mediated activation of NF-kappaB 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-kappaB for aberrant cell proliferation and simultaneously avoid apoptosis, thus implicating activated NF-kappaB as a therapeutic target for distinctive subclasses of ER-negative breast cancers.