Summary
The transcription factor Hypoxia inducible factor-1α (HIF-1α) plays a crucial role in tumor progression by regulating angiogenesis, cell survival and drug resistance. HIF-1α is also implicated in biological functions under normoxic conditions and recent data provide evidence for a possible role in tumor lymphangiogenesis by regulating the lymphatic vascular endothelial growth factor-C (VEGF-C). In breast cancer, lymphatic vessel invasion (LVI) by tumor cells and subsequent metastasis to axillary lymph nodes is a critical point in progression of the disease with severe therapeutical and prognostic implications. Aim of this study is to investigate the role of HIF-1α in VEGF-C expression, lymphangiogenesis, and LVI in lymph node positive breast cancer.
Lymphatic microvessel density (LMVD), LVI, HIF-1α and VEGF-C protein-expression were evaluated by immunohistochemistry in 119 cases of lymph node positive invasive breast cancer.
There was a significant correlation between HIF-1α and VEGF-C (p = 0.026, r = 0.204, Spearman’s coefficient of correlation). Further a significant association between HIF-1α-expression and the amount of peritumoral lymphangiogenesis LMVD was seen (p = 0.014, Mann–Whitney test). LMVD correlated significantly with LVI (p<0.001, Mann–Whitney test). HIF-1α was an independent prognostic factor for overall and disease free survival in uni- and multivariate analysis (p = 0.027, 0.029, 0.025, respectively, Cox regression).
Our data provide evidence for a possible role of HIF-1α as regulator of tumor-associated lymphangiogenesis in human breast cancer and emphasizes the promising status of HIF-1α as a therapeutical target against tumor progression and metastasis.