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Expression of endothelial and inducible nitric oxide synthase in benign and malignant lesions of the breast and measurement of nitric oxide using electron paramagnetic resonance spectroscopy
Author(s) -
Loibl Sibylle,
von Minckwitz Gunter,
Weber Sonja,
Sinn HansPeter,
SchiniKerth Valérie B.,
Lobysheva Irina,
Nepveu Françoise,
Wolf Georg,
Strebhardt Klaus,
Kaufmann Manfred
Publication year - 2002
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.10817
Subject(s) - nitric oxide synthase , pathology , immunohistochemistry , medicine , endothelial nos , nitric oxide , cancer research , enos
BACKGROUND Nitric oxide (NO) is present in various human solid tumors and tumor cell lines, and it is believed that NO plays an important role in tumor growth. An increased NO concentration catalyzed by NO synthase (NOS) is cytotoxic and can promote apoptosis. The expression of endothelial NOS (e‐NOS) and induced NOS (i‐NOS) was examined in various breast tumors. METHODS Immunohistochemical staining with a monoclonal antibody (Ab) against e‐NOS and a polyclonal Ab against i‐NOS was performed on paraffin embedded tissues from 41 benign breast lesions, 9 in situ breast lesions, and 54 invasive breast lesions. Functionality was confirmed by detection of NO using spin‐trapping electron paramagnetic resonance (EPR) spectroscopy. RESULTS e‐NOS expression was found in 2 benign lesions (5%; 1 fibroadenoma and 1 proliferative mastopathy), in 5 in situ lesions (56%), and in 33 invasive lesions (61%). None of the benign lesions was positive for i‐NOS, but 6 in situ lesions (67%) and 33 invasive lesions (61%) showed tumor cell staining. In particular, capillaries that were embedded in lymphocytic stroma showed a positive reaction for e‐NOS. The functionality of NOS was demonstrated by direct NO formation using the EPR spin‐trapping method. Tumors that were positive for e‐NOS were observed more often in younger patients ( P = 0.05). These tumors more frequently were highly differentiated or moderately differentiated and more often showed invasive ductal subtypes and a lower proliferation rate. Tumors that were positive for both e‐NOS and i‐NOS were more likely to be lymph node negative tumors. Both i‐NOS‐expressing lesions and e‐NOS‐expressing lesions showed strong coexpression ( P = 0.00001). CONCLUSIONS NOS is detected predominantly in in situ lesions and invasive breast lesions but rarely in benign lesions. NOS is found more frequently in invasive carcinomas with low malignancy. Using the spin‐trapping EPR method, this study demonstrates direct NO formation in human breast tumors for the first time. Cancer 2002;95:1191–8. © 2002 American Cancer Society. DOI 10.1002/cncr.10817