| Globally there is a significant increase in the number of breast cancer patients that present with skeletal related events (SREs) annually. Bone is a common site for breast cancer metastasis; and complications, such as pain, fractures and hypercalcemia, significantly increase the morbidity associated with disease. We recently identified Parathyroid Hormone-related Protein(12-48), PTHrP(12-48), as a biomarker in the circulation of breast cancer patients that correlates with and predicts bone metastasis [1]. Similarly, we have also shown that the cytokine interleukin 8 (IL-8/CXCL8) is highly expressed in human metastatic breast cancer cells [2, 3] and IL-8 levels are significantly correlated with increased bone resorption, as detected by elevated N-telopeptide (NTx) in these patients [4]. In this study, we investigated the signaling pathways and the resultant biologic function of IL-8 and PTHrP(12-48). In vitro, IL-8, acts via its cognate G-protein coupled receptor, CXCR1, and signals via activation of the NFkappaB, ERK, P38 and AKT pathways to induce osteoclastogenesis. No positive effects of PTHrP(12-48) interaction with the PTH1 receptor (PTHR1) were predicted by molecular modeling or observed in any physiologic setting evaluated, such as cAMP stimulation. However, PTHrP(12-48) translocates into cells, including human PTHR1-expressing, SaOS2 cells, and PTHR1-non-expressing, primary human osteoclasts, and induces apoptosis as measured by activation of caspase 3. The pro-osteoclastogenic activity of IL-8 was demonstrated in two transgenic mouse models expressing human IL-8 in vivo. The idea that these two tumor-related molecules represent novel ways to regulate the tumor-host microenvironment was tested throughout the course of this dissertation. Collectively, the data suggest that circulating IL-8 and PTHrP(12-48) are breast cancer-derived products that play important, yet distinct roles in osteoclast and tumor biology. |
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