Cells Regulate Tumor Burden and Osteolysis in Bone Dependent Mechanisms in Breast Cancer

A central mediator of a wide host of target genes, the nuclear factor-KB (NF-KB) family of transcription factors, has emerged as a molecular target in cancer and diseases associated with bone destruction. To evaluate how NF-KB signaling in tumor cells regulates processes associated with osteolytic bone tumor burden, we stably infected the boneseeking MDA-MB-231 breast cancer cell line with a dominant-negative mutant IKB that prevents phosphorylation of IKBa and associated nuclear translocation of NF-KB. Blockade of NF-KB signaling in MDA-MB-231 cells by the mutant IKB 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-KB 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 MDAMB-231 cells express both interleukin-6 and the p65 subunit of NF-KB at the bone-tumor interface. NF-KB 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-KB and its associated genes may be relevant therapeutic targets in osteolytic tumor burden. (Cancer Res 2005; 65(8): 3209-17)