Inducible nitric oxide synthase expression, apoptosis, and angiogenesis inin situ and invasive breast carcinomas

In this investigation, we studied the expression of inducible nitric oxide synthase (iNOS) and its association to apoptosis and angiogenesis in 43 in situ and 68 invasive breast carcinomas, Its expression was studied immunohi stochemically using a polyclonal iNOS antibody, and the staining was evalua ted both in tumor and stromal cells, Apoptosis was detected by 3' end label ing of fragmented DNA (terminal deoxynucleotidyl transferase-mediated nick end labeling method), Vascularization was detected immunohistochemically us ing an antibody to the FVIII-related antigen, and calculated microvessel de nsities were determined, In addition to strong iNOS expression in stromal c ells, iNOS positivity was observed in tumor cells in 46.5% of in situ and 5 8.8% of invasive carcinomas, In invasive carcinomas, there were more cases with iNOS positivity both in tumor and stromal cells compared to in situ ca rcinomas (0.007), The proportion of cases with iNOS-positive tumor cells in creased in irt situ carcinomas from grade I to III (20.0%, 46.2%, and 73.3% ). In invasive ductal carcinomas, there were more cases with iNOS-positive tumor cells than with in situ carcinomas (P = 0.03), Carcinomas with both i NOS-positive tumor and stromal cells had a higher apoptotic index (P = 0.02 ) and a higher calculated microvessel densities index (P = 0.02), A high nu mber of iNOS-positive stromal cells associated with metastatic disease (P = 0.05), The results show that breast carcinoma cells, in addition to stroma l cells, express iNOS and are capable of producing NO, Carcinomas with iNOS -positive tumor and stromal cells have a higher apoptotic indices and incre ased vascularization, suggesting that iNOS contributes to promotion of apop tosis and angiogenesis in breast carcinoma, The association of the number o f iNOS-positive stromal cells with metastatic disease might be attributable to stimulation of angiogenesis, resulting in a higher vascular density and consequently a higher probability for tumor cells to Invade.