Endothelial cell nitric oxide synthase in peritumoral microvessels is a favorable prognostic indicator in premenopausal breast cancer patients.
Nitric oxide (NO) is involved in tumor cell apoptosis and has additional effects on tumor blood flow, immune responses, and angiogenesis. We, therefore, studied endothelial cell NO synthase (ecNOS) protein expression in a retrospective series of 118 patients with primary invasive breast cancer. Immunocytochemically stained paraffin sections were used for determining the frequency of (a) tumor cells, (b) intratumoral microvessels, and (c) peritumoral microvessels that were positive for ecNOS. A high density of ecNOS positive microvessels in the normal tissue surrounding the tumor (measured by the variable PEMVD) was associated with significantly better recurrence-free and overall survival. The prognostic significance was observed in a representative series of premenopausal patients and was independent of other factors, including lymph node status. The counting procedure was highly reproducible and correlated to stereological measurements but was influenced by heterogeneity of the tissue samples. Analyzing two sections per patient improved the discriminative power by reducing the influence of tissue heterogeneity and produced highly significant results (recurrence-free survival, P < 0.001; overall survival, P < 0.0001). Immunoreactive ecNOS in microvessels is an independent prognostic factor in breast cancer and may reflect a mechanism of endothelial defense against invasion by tumor cells. Individual variations in ecNOS may be related to environmental, hormonal, and genetic factors and could represent a therapeutic target.
Mortensen
K
K
Department of Molecular Cell Biology, Statens Serum Institut, Copenhagen, Denmark.
Holck
S
S
Christensen
I J
IJ
Skouv
J
J
Hougaard
D M
DM
Blom
J
J
Larsson
L I
LI
D000328:Adult; D001943:Breast Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000401:mortality; D002196:Capillaries / Q000201:enzymology*; D018270:Carcinoma, Ductal, Breast / Q000098:blood supply / Q000201:enzymology* / Q000401:mortality; D018572:Disease-Free Survival; D004730:Endothelium, Vascular / Q000201:enzymology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007527:Isoenzymes / Q000032:analysis*; D015993:Life Tables; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis*; D019001:Nitric Oxide Synthase / Q000032:analysis*; D052250:Nitric Oxide Synthase Type III; D017697:Premenopause; D011379:Prognosis; D011897:Random Allocation; D015203:Reproducibility of Results; D012189:Retrospective Studies; D016019:Survival Analysis
D007527:Isoenzymes; D009363:Neoplasm Proteins; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III