Hypoxia-inducible factor 1alpha is closely linked to an aggressive phenotype in breast cancer

Breast Cancer Res Treat. 2008 Aug;110(3):465-75. doi: 10.1007/s10549-007-9742-1. Epub 2007 Sep 6.


Purpose: The aim of this study is to clarify characteristics of invasive breast cancer with expression of Hypoxia-induced factor 1alpha (HIF-1alpha) which is induced by hypoxia and signal transduction of growth factors.

Experimental design: We examined, by immunohistochemical analysis, the expression of HIF-1alpha in normal breast tissue, benign disorders and breast cancer. In invasive breast cancer, we investigated the correlation between expression of HIF-1alpha and clinicopathological and biological factors. We also studied the prognostic value of HIF-1alpha in breast cancer.

Results: HIF-1alpha was mainly detected in tumor cell nuclei. In the 171 cases of invasive breast cancer examined, nuclear HIF-1alpha expression was detected in 63 (36.8%) cases. Immunoreactive nuclear HIF-1alpha was correlated with tumor size (p = 0.0013), lymph node metastasis (p = 0.0005), tumor stage (p = 0.0031) and histological grade (p = 0.0074). Elevated HIF-1alpha levels was also associated with hormone receptor negativity (p = 0.0025), HER2 overexpression (p = 0.0053), high Ki67 labeling index (p = 0.0002), increased levels of VEGF (p < 0.0001), COX-2 overexpression (p = 0.0029) and increased nuclear p53 (p = 0.0048). In terms of the possible use of HIF-1alpha as a prognostic indicator, patients who had increased HIF-1alpha levels in their tumor showed shorter disease-free survival (DFS) (p < 0.0001) and overall survival (OS) (p = 0.0002) than those lacking HIF-1alpha in univariate analysis. In multivariate analysis of DFS and OS, HIF-1alpha was identified an independent prognostic factor.

Conclusions: These findings suggest that HIF-1alpha was closely linked to an aggressive phenotype in breast cancer. It may be useful to study the expression of HIF-1alpha using immunohistochemical analysis for better understanding of the tumor characteristics of breast cancer.

MeSH terms

  • Biomarkers, Tumor / analysis*
  • Breast Diseases / metabolism
  • Breast Diseases / pathology*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • Carcinoma, Ductal, Breast / metabolism
  • Carcinoma, Ductal, Breast / mortality
  • Carcinoma, Ductal, Breast / pathology*
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis*
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Middle Aged
  • Phenotype


  • Biomarkers, Tumor
  • Hypoxia-Inducible Factor 1, alpha Subunit