Hypoxia-induced factor-1 alpha upregulates vascular endothelial growth factor C to promote lymphangiogenesis and angiogenesis in breast cancer patients

Hypoxia-induced factor-1 alpha （HIF-1α） affects many effector molecules and regulates tumor lymphangio- genesis and angiogenesis during hypoxia. The aim of this study was to investigate the role of HIF-1α in the regu- lation of vascular endothelial growth factor C （VEGF-C） expression and its effect on lymphangiogenesis and an- giogenesis in breast cancer. Lymphatic vessel density （LVD）, microvessel density （MVD） and the expressions of HIF-1α and VEGF-C proteins were evaluated by immunohistochemistry in 75 breast cancer samples. There was a significant correlation between HIF-1α and VEGF-C （P = 0.014, r = 0.273, Spearman＇s coefficient of correlation）. HIF-1α and VEGF-C overexpression was significantly correlated with higher LVD （P = 0.003 and P = 0.017, re- spectively）, regional lymph nodal involvement （P = 0.002 and P = 0.004, respectively） and advanced tumor, node, metastasis （TNM） classification （P = 0.001 and P = 0.01, respectively）. Higher MVD was observed in the group expressing higher levels of HIF-1α and VEGF-C （P = 0.033 and P = 0.037, respectively）. Univariate analysis showed shorter survival time in patients expressing higher levels of HIF-1α and VEGF-C. HIF-1α was also found to be an independent prognostic factor of overall survival in multivariate analysis. The results suggest that HIF-1α may affect VEGF-C expression, thus acting as a crucial regulator of lymphangiogenesis and angiogenesis in breast cancer. This study highlights promising potential of HIF- 1α as a therapeutic target against tumor lymph node me- tastasis.