Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans.

Skeletal metastases of breast cancer and subsequent osteolysis connote a dramatic change in the prognosis for the patient and significantly increase the morbidity associated with disease. The cytokine interleukin 8 (IL-8/CXCL8) is able to directly stimulate osteoclastogenesis and bone resorption in mouse models of breast cancer bone metastasis. In this study, we determined whether circulating levels of IL-8 were associated with increased bone resorption and breast cancer bone metastasis in patients and investigated IL-8 action in vitro and in vivo in mice. Using breast cancer patient plasma (36 patients), we identified significantly elevated IL-8 levels in bone metastasis patients compared with patients lacking bone metastasis (p<0.05), as well as a correlation between plasma IL-8 and increased bone resorption (p<0.05), as measured by NTx levels. In a total of 22 ER+ and 15 ER- primary invasive ductal carcinomas, all cases examined stained positive for IL-8 expression. In vitro, human MDA-MB-231 and MDA-MET breast cancer cell lines secrete two distinct IL-8 isoforms, both of which were found to stimulate osteoclastogenesis. However, the more osteolytic MDA-MET-derived full length IL-8(1-77) had significantly higher potency than the non-osteolytic MDA-MB-231-derived IL-8(6-77), via the CXCR1 receptor. MDA-MET breast cancer cells were injected into the tibia of nude mice and 7days later treated daily with a neutralizing IL-8 monoclonal antibody. All tumor-injected mice receiving no antibody developed large osteolytic bone tumors, whereas 83% of the IL-8 antibody-treated mice had no evidence of tumor at the end of 28days and had significantly increased survival. The pro-osteoclastogenic activity of IL-8 in vivo was confirmed when transgenic mice expressing human IL-8 were examined and found to have a profound osteopenic phenotype, with elevated bone resorption and inherently low bone mass. Collectively, these data suggest that IL-8 plays an important role in breast cancer osteolysis and that anti-IL-8 therapy may be useful in the treatment of the skeletal related events associated with breast cancer.

Elevated bone turnover predicts for bone metastasis in postmenopausal breast cancer: results of NCIC CTG MA.14.

PURPOSE: We investigated the association of bone-only relapse with a pretreatment marker of bone resorption: serum beta C-terminal telopeptide (B-CTx) of type I collagen. METHODS: Pretreatment serum B-CTx concentrations were determined from 621 of 667 patients with primary breast cancer enrolled onto the NCIC CTG MA.14 phase III adjuvant trial of tamoxifen with or without octreotide. Recurrence-free survival (RFS) was a secondary end point; the focus here was bone-only relapse. We analyzed continuous or categorical (.71 ng/mL cut point) serum B-CTx in stepwise forward multivariate Cox regression, adjusted for trial stratification factors. We also examined B-CTx and bone relapse by pretrial chemotherapy status. RESULTS: At median 7.9 years follow-up, 123 of 621 patients experienced recurrence; 19 (3.1%) of 621 had bone-only recurrence, and 47 (7.5%) of 621 had bone plus other sites of recurrence. Larger pathologic tumor size (P = .001) and elevated continuous and categorical serum B-CTx were associated with shorter bone-only RFS (both P = .02) when added to a model with factors significant in the main trial analyses (hazard ratio [HR], 3.43 and 3.50, respectively; 95% CI, 1.20 to 9.77 and 1.26 to 9.75, respectively). The univariate HR for B-CTx was 2.80 (95% CI, 1.05 to 7.48; P = .03). Elevated serum B-CTx was also associated with shorter bone-only RFS (P = .02) when added to a model with factors significant in the main trial analyses. Serum B-CTx level was not associated with any other type of recurrence. Serum B-CTx was not significantly different for patients who underwent pretrial chemotherapy, compared with those who did not (P = .27), nor did pretrial chemotherapy affect bone relapse (P = .48 for bone only; P = .76 for bone with other relapse). CONCLUSION: Higher pretreatment serum B-CTx was a significant predictor of shorter RFS for bone-only metastasis. Increased bone resorption creates an environment that promotes growth of breast cancer cells.