Nuclear factor-kappaB activation: a molecular therapeutic target for estrogen receptor-negative and epidermal growth factor receptor family receptor-positive human breast cancer.
Nuclear factor-kappaB (NF-kappaB), 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-kappaB in ER-negative breast cancer cells and breast tumor specimens, but the consequence of inhibiting NF-kappaB activation in this subclass of breast cancer has not been shown. In this study, we investigated the role of NF-kappaB activation by studying the tumorigenic potential of cells expressing genetically manipulated, inducible, dominant-negative inhibitory kappaB kinase (IKK) beta in xenograft tumor model. Conditional inhibition of NF-kappaB activation by the inducible expression of dominant-negative IKKbeta 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-kappaB essential modifier-binding domain peptide both blocked NF-kappaB 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-kappaB activation with two other low molecular weight compounds, PS1145 and PS341, which inhibited IKK activity and proteasome-mediated phosphorylated inhibitory kappaB protein degradation, respectively, blocked erbB2-mediated cell growth and reversed antiapoptotic machinery. These results implicate NF-kappaB 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.
Singh
Sindhu
S
Department of Cancer Biology, Dana-Farber Cancer Institute, Smith Room 1058, 44 Binney Street, Boston, MA 02115, USA.
Shi
Qian
Q
Bailey
Shannon T
ST
Palczewski
Marek J
MJ
Pardee
Arthur B
AB
Iglehart
J Dirk
JD
Biswas
Debajit K
DK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000145:classification / Q000378:metabolism* / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D011960:Receptors, Estrogen / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D051550:I-kappa B Kinase; D016328:NF-kappa B; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen