Expression of Vascular Endothelial Growth Factor Subtypes in Mammary Invasive Ductal Carcinoma and their Relationship to Tumor Progression

Abstract

Context:Multiple genes and proteins have been shown to be important in treatment and prognosis of breast cancer, including the estrogen and progesterone receptors and Her-2 neu. Vascular endothelial growth factor (VEGF) subtypes have been shown to be associated with lympho-vascular invasion, lymph node metastases and prognosis in multiple types of cancer, including colon cancer, gastric cancer and breast cancer. The goal of this project was to observe and quantify the protein expression of VEGF subtypes in human breast cancer, then correlate this with known clinicopathologic information. Design:Ninety grade three (high grade) invasive ductal carcinomas received over a four year period (1997-2001) were selected from our files. Immunohistochemistry was performed on formalin fixed paraffin embedded tissue of both primary tumor and lymph node metastasis when applicable using VEGF-A, VEGF-C, VEGF-D and VEGF-R (the VEGF receptor) antibodies. The staining was graded from zero (no expression) to 3+ (high expression). These expression profiles were then compared via Chi-Square test to known information about the patients and tumors including lympho-vascular invasion (LVI), lymph node metastases (LNM), stage of the tumor at diagnosis and cancer recurrence. Results: A high level (3+) of VEGF-A, VEGF-D and VEGF-R expression was seen in 43 (47.8%), 32 (35.6%), and 24 (26.7%), cases respectively; expression of VEGF-C was seen in 7 (7.8%) of cases. Normal residual breast tissue was either negative or showed 1+ to 2+ staining. A high level of VEGF-A expression and the presence of VEGF-C expression were both associated with tumor recurrence (p Conclusions:In high grade invasive ductal carcinoma, strong VEGF-A, VEGF-C and VEGF-R protein expression was associated with adverse prognostic factors, including lymph node metastases, higher TNM stage and cancer recurrence. These results imply that further study of these proteins and their quantification in tissue samples may help in predicting long-term prognosis of patients with breast cancer. References Choi, William et al. Angiogenic and lymphangiogenic microvessel density in breast carcinoma: correlation with clinicopathologic parameters and VEGF-family gene expression. Modern Pathology 2005; 18: 144-152. Ferrara, Napeone, Gerber, Hans-Peter and LeCouter, Jennifer. The biology of VEGF and its receptors. Nature Medicine 2003; 9: 669-676. Jain, Rakesh et al. Lessons from phase III clinical trails on anti-VEGF therapy for cancer. Nature Clinical Practice Oncology 2006; 1: 24-40. Jeltsch, Michael et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 1997; 276: 1423-1425. Kurebayashi, Junichi et al. Expression of vascular endothelial growth factor (VEGF) family members in breast cancer. Japanses Journal of Cancer Research 1999; 90: 977-981. Nakamura, Yasushi et al. Prognostic significance of vascular endothelial growth factor D in breast carcinoma with long-term follow-up. Clinical Cancer Research 2003; 9: 716-721. Onogawa, Seiji et al. Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in early gastric carcinoma: correlation with clinicopathologic parameters. Cancer Letters 2005; 226: 85-90. Ribeiro-Silva, Alfredo et al. Vascular endothelial growth factor expression in the basal subtype of breast carcinoma. American Journal of Clinical Pathology 2006; 125: 512-518. Schoppmann, Sebastian et al. Hypoxia inducible factor 1-α correlates with VEGF-C expression in lymphangiogenesis in breast cancer. Breast Cancer Research and Treatment 2006. Shida, Atsuo et al. Expression of vascular endothelial growth factor (VEGF)-C and –D in gastric carcinoma. International Journal of Clinical Oncology 2006; 11: 38-43. Skobe, Mihaela et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nature Medicine 2001; 7: 192-198. Stacker, Steven et al. Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. The Journal of Biological Chemistry 1999; 274: 32127-32136. Stacker, Steven et al. VEGF-D promotes metastatic spread of tumor cells via the lymphatics. Nature Medicine 2001; 7: 186-191.