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Nuclear Factor-B–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone

¹ Biomedical Engineering, University of Rochester and ² Department of Orthopaedics and Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, New York

Requests for reprints: J. Edward Puzas, Department of Orthopaedics and Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 665, Rochester, NY 14642. Phone: 585-275-3664; Fax: 585-756-4727; E-mail: Edward_Puzas{at}URMC.Rochester.edu.

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