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mica, survivin, and rankl transcript levels in tumor biopsies were analyzed by real-time rt-pcr and compared with those in tumor samples obtained from patients with diabetes (n=32) and no evidence of vasculitis (nova group, n=31). for the nova group, the median survival time was 26 days as compared to 24 days (p = 0.08), while all patients in the nova group survived for more than 1 year as compared to patients in the non-nova group (p = 0.02). the 6-month post-operative mortality rate in the nova group was 13.8% as compared to 29.0% in the non-nova group (p = 0.12).

hypoxia-induced cytokine signaling was examined by using a variety of cytokines. among these, il-1 and tnf-alpha secreted by the breast epithelial cells were shown to induce an increase in the promoter activity of erbb2 in mda-mb-453 cells. an increase in erbb2 expression was observed in breast cancer cells in vitro by analyzing the mrna and protein levels by using rt-pcr and western blot. furthermore, an increase in erbb2 protein levels was also found in vivo in a breast cancer xenograft model. by immunohistochemical analysis of breast cancer samples, we observed that upregulation of erbb2 is often associated with an aggressive phenotype of breast cancer and hypoxia-induced tumorigenesis. the results reported here demonstrate that the il-1/tnf-alpha-induced cytokine signaling that targets the erbb2 promoter is a novel mechanism by which hypoxia regulates breast tumor progression. hypoxia-induced cytokine signaling may play an important role in the progression of erbb2 overexpressing breast cancer cells.

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