| Skeletal metastasis is frequently observed in patients with advanced breast cancer. As many as one-third of women with early-stage breast cancer will eventually succumb to the disease, most of whom will develop complications arising from bone metastases, including severe pain, hypercalcemia, and pathologic fracture. Identification and development of novel genetic and pharmacotherapeutic approaches with the potential to reduce or prevent metastatic tumor burden in bone will plausibly ameliorate these otherwise devastating clinical symptoms. The general aim of this research effort was to better understand how NFκB signaling affects the underlying tendency of breast cancer cells with a bone-seeking phenotype to stimulate tumor-mediated bone destruction. A central mediator in expression of a wide host of target genes, the nuclear factor kappa B (NFκB) family of transcription factors has emerged as a promising molecular target in cancer and diseases associated with bone destruction. NFκB signaling mediates gene expression of a variety of cytokines, adhesion molecules, acute phase response proteins, and Rel-IκB proteins capable of influencing the biochemical and biophysical phenomena associated with breast cancer metastasis to bone. Here a dominant negative mutant IκB (mIκB) was stably infected in the MDA-MB-231 breast cancer cell line to evaluate how NFκB transcription regulates the ability of these tumor cells to secrete factors implicated in skeletal metastasis and stimulate associated osteolytic bone destruction. NFκB activation in MDA-MB-231 breast cancer cells was demonstrated to regulate cell survival and growth, expression of high basal levels of the proinflammatory, bone-resorbing cytokine IL-6, as well as associated in vitro bone resorption and in vivo tumor-mediated osteolysis by these tumor cells. These findings elucidate how NFκB signaling in breast cancer cells tightly controls their capacity to promote vicious cycles of tumor-mediated osteolysis within the bone microenvironment. NFκB, IL-6, and associated signaling pathways, therefore, may serve as potential therapeutic targets in the clinical management of breast cancer-mediated osteolysis. |
