Akt activation has been found in various human cancers, while experimental studies have suggested that Akt plays an important role in the development of tumor angiogenesis and lymphangiogenesis. Immunohistochemical analyses for VEGF-C and Akt and the lymphatic endothelial specific marker D2-40 were performed on a series of 242 invasive ductal carcinomas of the breast, in which VEGF-A expression and microvessel density (MVD) had been determined previously. Lymphatic vessel density (LVD) was estimated in three hot spots. A significant correlation was observed between the VEGF-C expression and LVD (p=0.0026) and between LVD and the lymph node status (p<0.0001). The VEGF-C expression, however, did not correlate significantly with the lymph nodes status, while a high VEGF-C expression was associated with a smaller tumor size (p=0.0188). There was a significant correlation between VEGF-C and VEGF-A expression (p=0.0079) and between LVD and MVD (p=0.0008). The VEGF-C expression correlated with MVD (p<0.0001), while the VEGF-A expression correlated with LVD (p=0.0155). The Akt expression correlated with VEGF-A (p=0.0173) and -C expression (p=0.0056) as well as MVD (p=0.0482) and LVD (p=0.0012), while the correlation of Akt expression to VEGF-C expression and LVD was stronger than that to VEGF-A expression and MVD. Although the patients with a high LVD have a poorer disease-free survival than those with a low LVD (p=0.0005), a multivariate analysis determined the lymph node status and MVD to be independently significant factors for the disease-free survival. In conclusion, the correlation of both VEGF-C and VEGF-A to LVD and MVD suggested the two growth factors to be involved in both angiogenesis and lymphangiogenesis in breast cancer. The correlation of the Akt expression to the VEGF-A and -C expression as well as MVD and LVD, thus, suggested Akt activation to contribute to both angiogenesis and lymphangiogenesis via VEGF-A and -C expression in breast cancer.

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