title: Hypoxia-inducible factor 1alpha is closely linked to an aggressive phenotype in breast cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Breast & Endocrine Surgery, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto 860-8556 Kumamoto, Japan. ys-yama@triton.ocn.ne.jp
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Ibusuki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Okumura
authors.forename: Teru
authors.initials: T
authors.lastname: Kawasoe
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Kai
authors.forename: Kenichi
authors.initials: K
authors.lastname: Iyama
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Iwase
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D001941:Breast Diseases / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D010641:Phenotype