for those her2+and ER- combining herceptin and a NFkappa beta inhibitor synergistic

[Lani]

Published online before print June 25, 2004, 10.1073/pnas.0403621101
PNAS | July 6, 2004 | vol. 101 | no. 27 | 10137-10142
Medical Sciences
NF-B activation in human breast cancer specimens and its role in cell proliferation and apoptosis

Debajit K. Biswas *, , , Qian Shi *, Shanon Baily , Ian Strickland , Sankar Ghosh , Arthur B. Pardee , and J. Dirk Iglehart *, ¶

Departments of *Cancer Biology and Medical Oncology, Dana–Farber Cancer Institute, Boston, MA 02115; ¶Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115; and Section of Immunology and Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520

Contributed by Arthur B. Pardee, May 24, 2004


Lack of molecular targets in estrogen receptor-negative (ER-negative) breast cancer is a major therapeutic hurdle. We studied NF-B activation in human breast tumors and in carcinoma cell lines. Activated NF-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-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-B complex, in cytokeratin 19 (CK19)-positive epithelial cells of ER-negative/ErbB2-positive tumor samples. In contrast, nuclear NF-B was detected mostly in stroma of ER-negative and ErbB2-negative tumors, suggesting a role of activated NF-B in intercellular signaling between epithelial and stromal cells in this type of breast cancers. To elucidate roles of activated NF-B, we used an ER-negative and ErbB2-positive human breast tumor cell line (SKBr3). The polypeptide heregulin 1 stimulated, and herceptin, the anti-ErbB2 antibody, inhibited, NF-B activation in SKBr3 cells. The NF-B essential modulator (NEMO)-binding domain (NBD) peptide, an established selective inhibitor of IB-kinase (IKK), blocked heregulin-mediated activation of NF-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-B for aberrant cell proliferation and simultaneously avoid apoptosis, thus implicating activated NF-B as a therapeutic target for distinctive subclasses of ER-negative breast cancers.