Nuclear factor-κB-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-kappa B (NF-kappa B) family of transcription factors, has emerged as a molecular target in cancer and diseases associated with bone destruction. To evaluate how NF-kappa B 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 I kappa B that prevents phosphorylation of I kappa B alpha and associated nuclear translocation of NF-kappa B. Blockade of NF-kappa B signaling in MDA-MB-231 cells by the mutant I kappa B 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-kappa B 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-kappa B at the bone-tumor interface. NF-kappa B 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-kappa B and its associated genes may be relevant therapeutic targets in osteolytic tumor burden.