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 ef fects on tumor blood flow, immune responses, and angiogenesis, We, therefor e, studied endothelial cell NO synthase (ecNOS) protein expression in a ret rospective series of 118 patients with primary invasive breast cancer. Immu nocytochemically stained paraffin sections were used for determining the fr equency of (a) tumor cells, (b) intratumoral microvessels, and (c) peritumo ral microvessels that were positive for ecNOS, A high density of ecNOS posi tive microvessels in the normal tissue surrounding the tumor (measured by t he variable PEMVD) was associated with significantly better recurrence-free and overall survival. The prognostic significance was observed in a repres entative series of premenopausal patients and was independent of other fact ors, including lymph node status. The counting procedure was highly reprodu cible and correlated to stereological measurements but was influenced by he terogeneity of the tissue samples. Analyzing two sections per patient impro ved the discriminative power by reducing the influence of tissue heterogene ity 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 mech anism of endothelial defense against invasion by tumor cells. Individual va riations in ecNOS may be related to environmental, hormonal, and genetic fa ctors and could represent a therapeutic target.