title: Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma.
abstract: 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.
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Bos
authors.forename: Petra
authors.initials: P
authors.lastname: van der Groep
authors.forename: Astrid E
authors.initials: AE
authors.lastname: Greijer
authors.forename: Avi
authors.initials: A
authors.lastname: Shvarts
authors.forename: Sybren
authors.initials: S
authors.lastname: Meijer
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.forename: Elsken
authors.initials: E
authors.lastname: van der Wall
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000473:pathology*; D002277:Carcinoma / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000096:biosynthesis*; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008207:Lymphatic Metastasis; D008875:Middle Aged; D008940:Mitotic Index; D009687:Nuclear Proteins / Q000032:analysis / Q000096:biosynthesis*; D011237:Predictive Value of Tests; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis; D014157:Transcription Factors
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014157:Transcription Factors; C497442:HIF1A protein, human