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Endothelial Cell Nitric Oxide Synthase in Peritumoral Microvessels Is a Favorable Prognostic Indicator in Premenopausal Breast Cancer Patients¹

Department of Molecular Cell Biology, Statens Serum Institut, Copenhagen [K. M., D. M. H., J. B., L-I. L.]; Institute of Anatomy and Physiology, The Royal Veterinary and Agricultural University, DK-1870 Frederiksberg C [K. M., L-I. L.]; Department of Pathology, Hillerød Hospital, DK-3400 Hillerød [S. H.]; Finsen Laboratory, Rigshospitalet, DK-2100 Copenhagen [I. J. C.]; and Exiqon, DK-2950 Vedbæk [J. S.], Denmark

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.

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