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  • Title: Nuclear factor-kappaB-dependent mechanisms in breast cancer cells regulate tumor burden and osteolysis in bone.
    Author: Gordon AH, O'Keefe RJ, Schwarz EM, Rosier RN, Puzas JE.
    Journal: Cancer Res; 2005 Apr 15; 65(8):3209-17. PubMed ID: 15833852.
    Abstract:
    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.
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