127 P - TGF-b reduces nitric oxide production BT tumour associated macrophages

Previous studies have shown that the polyamine producing enzyme arginase, is increased in the serum of breast cancer patients. Tumour derived TGF-b has been found to inhibit nitric oxide production from macrophages in a methylcholanthrene induced tumour model. We hypothesised that TGF-b regulated arginine metabolism in the hypoxic environment of breast tumours. To determine the pathway of arginine utllilisation within tumours we measured nitric oxide production from both tumour associated macrophages and monocyte derived macrophages (MDMs). cultured in hypoxic conditions with TGF-b. Results TGF-b levels were significantly increased in the serum of malignant compared to benign breast cancer patients (101.17±14.9 vs 52.07±15.6 ng/ml p=.018), Tumour associated macrophages (TAMs) produce lower amounts of nitric oxide than normal tissue macrophages (2±3 vs 6.4±3 pM/Well/ug protein). MDMs cultured under hypoxic conditions in the presence of TGF-b produce less nitric oxide than those cultured with hypoxia alone (10±2 vs 30±7 pM/well/ug protein). Conclusions Taken together with evidence of increased arginase in these patients, this data indicates that arginine within breast tumours is diverted from the nitric oxide pathway, possibly to the polyamine producing arginase pathway. In this way increased arginase activity may promote tumour growth by providing polyamine substrates.