Expression of hypoxia-inducible factor (HIF-1α), VEGF-C and VEGF-D in non-invasive and invasive breast ductal carcinomas

Background: Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is a transcription factor that may play an important role in tumour growth and metastasis by its regulation of angiogenesis and lymphangiogenesis to survive cellular hypoxia. Lymphangiogenesis is promoted by vascular endothelial growth factors (VEGF)-C and VEGF-D, but the correlation between the expression of HIF-1 alpha and VEGF-C or VEGF-D in human breast carcinoma is not well elucidated. This study examined the pathobiological role of these molecules in human breast ductal carcinoma. Materials and Methods: The expressions of HIF-1 alpha, VEGF-C and VEGF-D were analyzed in 10 normal mammary epithelia, 12 fibroadenomas, 20 ductal carcinomas in situ (DCISs and 36 invasive ductal carcinomas (IDCs) by immunohistochemistry, comparing clinicopathological parameters. Results: HIF-1 alpha expression in nuclei was found in DCIS and IDC, but not in normal or fibroadenoma cells. The HIF-1 alpha labelling index was significantly correlated with the degree of VEGF-C expression in IDC (p < 0.001), but not in DCIS. HIF-1 alpha expression was significantly correlated with tumour necrosis and with the Van Nuys prognostic index (VNPI) (p < 0.05, p < 0.05, respectively) in the 20 DCISs. On the other hand, VEGF-D levels, but not those of HIF-1 alpha and VEGF-C, were significant higher in cases with lymph node metastasis and estrogen receptor expression in carcinoma cells (p < 0.01, p < 0.05, respectively) in the 36 IDCs. Conclusion: These findings suggest that HIF-1 alpha is expressed in the early stage of mammary carcinogenesis, in which the expression correlates with necrosis in the DCISs and with VEGF-C expression in the IDCs, the latter resulting in a higher frequency of metastasis to regional lymph nodes.