Hypoxia inducible factor-1alpha correlates with VEGF-C expression and lymphangiogenesis in breast cancer

Breast Cancer Res Treat. 2006 Sep;99(2):135-41. doi: 10.1007/s10549-006-9190-3. Epub 2006 Mar 23.


The transcription factor Hypoxia inducible factor-1alpha (HIF-1alpha) plays a crucial role in tumor progression by regulating angiogenesis, cell survival and drug resistance. HIF-1alpha 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-1alpha in VEGF-C expression, lymphangiogenesis, and LVI in lymph node positive breast cancer. Lymphatic microvessel density (LMVD), LVI, HIF-1alpha 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-1alpha and VEGF-C (p = 0.026, r = 0.204, Spearman's coefficient of correlation). Further a significant association between HIF-1alpha-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-1alpha 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-1alpha as regulator of tumor-associated lymphangiogenesis in human breast cancer and emphasizes the promising status of HIF-1alpha as a therapeutical target against tumor progression and metastasis.

MeSH terms

  • Adult
  • Aged
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / metabolism
  • Carcinoma, Ductal, Breast / secondary
  • Carcinoma, Lobular / metabolism
  • Carcinoma, Lobular / secondary
  • Disease-Free Survival
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Lymphangiogenesis*
  • Lymphatic Metastasis / pathology
  • Lymphatic Vessels / pathology*
  • Middle Aged
  • Neoplasm Invasiveness / pathology
  • Neoplasm Staging
  • Vascular Endothelial Growth Factor C / metabolism*


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • VEGFC protein, human
  • Vascular Endothelial Growth Factor C