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Nitric Oxide in Breast Cancer: Induction of Vascular Endothelial Growth Factor-C and Correlation with Metastasis and Poor Prognosis

Authors' Affiliations: ¹ Department of Pathology, Wakayama Medical University, Wakayama City, Wakayama, Japan and Departments of ² Pathology and ³ Surgery, Osaka Police Hospital, Osaka City, Osaka, Japan

Requests for reprints: Yasushi Nakamura, Department of Pathology, Wakayama Medical University, Kimiidera 811-1, Wakayama, Japan 641-8509. Phone: 81-73-441-0635; Fax: 81-73-446-4825; E-mail: ynakamur{at}wakayama-med.ac.jp.

Purpose: Metastasis to regional lymph nodes through the lymphatic vessels is a common step in the progression of cancer. Recent evidence suggests that tumor production of vascular endothelial growth factor-C (VEGF-C) promotes lymphagiogenesis, which in turn promotes lymphatic metastasis. Nitric oxide (NO) may also increase metastatic ability in human cancers.

Experimental Design: Nitrite/nitrate levels and VEGF-C production were assessed in MDA-MB-231 breast cancer cells after induction and/or inhibition of NO synthesis. Formation of nitrotyrosine, a biomarker for peroxynitrate formation from NO in vivo, was analyzed in primary human breast carcinoma with long-term follow-up. The relationship between nitrotyrosine levels and lymph node status, VEGF-C immunoreactivity, and other established clinicopathologic variables, as well as prognosis, was analyzed.

Results: Production of nitrite/nitrate and VEGF-C in MDA-MB-231 cells was increased by treatment with the NO donor DETA NONOate. The NO synthase inhibitor N^G-nitro-L-arginine methyl ester eliminated this increase. High-grade nitrotyrosine staining was observed in 57.5% (65 of 113) of the invasive breast carcinomas. Nitrotyrosine levels were significantly correlated with VEGF-C immunoreactivity and lymph node metastasis. Survival curves determined by the Kaplan-Meier method showed that high nitrotyrosine levels were associated with reduced disease-free and overall survival. In multivariate analysis, high nitrotyrosine levels emerged as a significant independent predictor for overall survival.

Conclusions: Our data showed a role for NO in stimulating VEGF-C expression in vitro. Formation of its biomarker nitrotyrosine was also correlated with VEGF-C expression and lymph node metastasis. Furthermore, high nitrotyrosine levels may serve as a significant prognostic factor for long-term survival in breast cancer.

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