title: Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis.
abstract: BACKGROUND
  Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates gene expression in critical pathways involved in tumor growth and metastases. In this report, we investigated whether the level of HIF-1 alpha is increased during carcinogenesis in breast tissue and is associated with other tumor biomarkers.
  
  
  METHODS
  Paraffin-embedded clinical specimens from five pathologic stages of breast tumorigenesis and from normal breast tissue were used. HIF-1 alpha protein and the biomarkers vascular endothelial growth factor (VEGF), HER-2/neu, p53, Ki-67, and estrogen receptor (ER) were identified immunohistochemically, and microvessel density (a measure of angiogenesis) was determined. Associations among levels of HIF-1 alpha and these biomarkers were tested statistically. All statistical tests are two-sided.
  
  
  RESULTS
  The frequency of HIF-1 alpha-positive cells in a specimen increased with the specimen's pathologic stage (P<.001, chi(2) test for trend) as follows: normal breast tissue (0 specimens with > or = 1% HIF-1 alpha-positive cells in 10 specimens tested), ductal hyperplastic lesions (0 in 10), well-differentiated ductal carcinomas in situ (DCIS) (11 in 20), well-differentiated invasive breast cancers (12 in 20), poorly differentiated DCIS (17 in 20), and poorly differentiated invasive carcinomas (20 in 20). Increased levels of HIF-1 alpha were statistically significantly associated with high proliferation and increased expression of VEGF and ER proteins. In DCIS lesions, increased levels of HIF-1 alpha were statistically significantly associated with increased microvessel density. HIF-1alpha showed a borderline association with HER-2/neu but no association with p53.
  
  
  CONCLUSIONS
  The level of HIF-1 alpha increases as the pathologic stage increases and is higher in poorly differentiated lesions than in the corresponding type of well-differentiated lesions. Increased levels of HIF-1 alpha are associated with increased proliferation and increased expression of ER and VEGF. Thus, increased levels of HIF-1 alpha are potentially associated with more aggressive tumors.
authors.affiliation: Department of Pathology, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Bos
authors.forename: H
authors.initials: H
authors.lastname: Zhong
authors.forename: C F
authors.initials: CF
authors.lastname: Hanrahan
authors.forename: E C
authors.initials: EC
authors.lastname: Mommers
authors.forename: G L
authors.initials: GL
authors.lastname: Semenza
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: M D
authors.initials: MD
authors.lastname: Abeloff
authors.forename: J W
authors.initials: JW
authors.lastname: Simons
authors.forename: P J
authors.initials: PJ
authors.lastname: van Diest
authors.forename: E
authors.initials: E
authors.lastname: van der Wall
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D016228:Endothelial Growth Factors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; D008222:Lymphokines; D009687:Nuclear Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C497442:HIF1A protein, human