Nuclear factor-kappaB-dependent mechanisms in breast cancer cells regulate tumor burden and osteolysis in bone.
A central mediator of a wide host of target genes, the nuclear factor-kappaB (NF-kappaB) family of transcription factors, has emerged as a molecular target in cancer and diseases associated with bone destruction. To evaluate how NF-kappaB signaling in tumor cells regulates processes associated with osteolytic bone tumor burden, we stably infected the bone-seeking MDA-MB-231 breast cancer cell line with a dominant-negative mutant IkappaB that prevents phosphorylation of IkappaBalpha and associated nuclear translocation of NF-kappaB. Blockade of NF-kappaB signaling in MDA-MB-231 cells by the mutant IkappaB decreased in vitro cell proliferation, expression of the proinflammatory, bone-resorbing cytokine interleukin-6, and in vitro bone resorption by tumor/osteoclast cocultures while reciprocally up-regulating production of the proapoptotic enzyme caspase-3. Suppression of NF-kappaB transcription in these breast cancer cells also reduced incidence of in vivo tumor-mediated osteolysis after intratibial injection of tumor cells in female athymic nude mice. Immunohistochemistry showed that the cancerous lesions formed in bone by MDA-MB-231 cells express both interleukin-6 and the p65 subunit of NF-kappaB at the bone-tumor interface. NF-kappaB signaling in breast cancer cells therefore promotes bone tumor burden and tumor-mediated osteolysis through combined control of tumor proliferation, cell survival, and bone resorption. These findings imply that NF-kappaB and its associated genes may be relevant therapeutic targets in osteolytic tumor burden.
Gordon
Andrew H
AH
Biomedical Engineering, University of Rochester, Rochester, NY 14642, USA.
O'Keefe
Regis J
RJ
Schwarz
Edward M
EM
Rosier
Randy N
RN
Puzas
J Edward
JE
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D001862:Bone Resorption / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics; D007763:Lac Operon; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic
D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B