Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma

Cancer. 2003 Mar 15;97(6):1573-81. doi: 10.1002/cncr.11246.


Background: Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis to survive cellular hypoxia. Increased levels of HIF-1alpha, the O(2)-regulated subunit of HIF-1, were noted during breast carcinogenesis. In this study, the prognostic value of HIF-1alpha expression and its correlation with various clinicopathologic variables in patients with invasive breast carcinoma were investigated.

Methods: Expression levels of HIF-1alpha, HER-2/neu, estrogen receptor, and progesterone receptor were analyzed in 150 patients with early-stage breast carcinoma by immunohistochemistry. HER-2/neu gene amplification was investigated with automated fluorescent in situ hybridization. The mitotic activity index, histologic grade, and tumor type were assessed in hematoxylin and eosinstained specimens. Clinical data included disease-free survival, overall survival, lymph node status, and tumor size. The data were analyzed with two-sided univariate and multivariate tests, with P values < 0.05 considered significant.

Results: High levels of HIF-1alpha had an association of borderline significance with decreased overall survival (P = 0.059) and disease-free survival (P = 0.110) that was ascribed completely to the subgroup of women with lymph node negative tumors (n = 81 patients; P = 0.008 and P = 0.004, respectively). HER-2/neu immunoreactivity (P < 0.001) and gene amplification (P < 0.001), vascular endothelial growth factor expression (P = 0.016), and Ki-67 expression (P < 0.001) were correlated strongly with HIF-1alpha positivity, although none of those factors had an independent effect on survival.

Conclusions: Increased levels of HIF-1alpha were associated independently with shortened survival in patients with lymph node negative breast carcinoma. Therefore, the use of immunohistochemical assessment of HIF-1alpha as a new predictor of poor outcome may improve clinical decision-making regarding adjuvant treatment of patients with lymph node negative breast carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / analysis*
  • Breast Neoplasms / pathology*
  • Carcinoma / pathology*
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / biosynthesis*
  • Disease-Free Survival
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic*
  • Helix-Loop-Helix Motifs
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Lymphatic Metastasis
  • Middle Aged
  • Mitotic Index
  • Nuclear Proteins / analysis
  • Nuclear Proteins / biosynthesis*
  • Predictive Value of Tests
  • Prognosis
  • Receptor, ErbB-2 / biosynthesis
  • Receptors, Estrogen / biosynthesis
  • Receptors, Progesterone / biosynthesis
  • Transcription Factors


  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Transcription Factors
  • Receptor, ErbB-2