title: Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease.
abstract: BACKGROUND
  The precise timing of the angiogenic switch and the role of angiogenesis in the development of breast malignancy is currently unknown.
  
  
  METHODS
  Therefore, the expression of CD31 (pan endothelial cells (ECs)), endoglin (actively proliferating ECs), hypoxia-inducible factor-1 (HIF-1alpha), vascular endothelial growth factor-A (VEGF) and tissue factor (TF) were quantified in 140 surgical specimens comprising normal human breast, benign and pre-malignant hyperplastic tissue, in situ and invasive breast cancer specimens.
  
  
  RESULTS
  Significant increases in angiogenesis (microvessel density) were observed between normal and benign hyperplastic breast tissue (P<0.005), and between in situ and invasive carcinomas (P<0.0005). In addition, significant increases in proliferating ECs were observed in benign hyperplastic breast compared with normal breast (P<0.05) cancers and in invasive compared with in situ cancers (P<0.005). Hypoxia-inducible factor-1alpha, VEGF and TF expression were significantly associated with increases in both angiogenesis and proliferating ECs (P<0.05). Moreover, HIF-1alpha was expressed by 60-75% of the hyperplastic lesions, and a significant association was observed between VEGF and TF in ECs (P<0.005) and invasive tumour cells (P<0.01).
  
  
  CONCLUSIONS
  These findings are the first to suggest that the angiogenic switch, associated with increases in HIF-1alpha, VEGF and TF expression, occurs at the onset of hyperplasia in the mammary duct, although the greatest increase in angiogenesis occurs with the development of invasion.
authors.affiliation: Microcirculation Research Group, Academic Unit of Surgical Oncology, University of Sheffield Medical School, Sheffield, South Yorkshire, UK.
authors.forename: J E
authors.initials: JE
authors.lastname: Bluff
authors.forename: S R
authors.initials: SR
authors.lastname: Menakuru
authors.forename: S S
authors.initials: SS
authors.lastname: Cross
authors.forename: S E
authors.initials: SE
authors.lastname: Higham
authors.forename: S P
authors.initials: SP
authors.lastname: Balasubramanian
authors.forename: N J
authors.initials: NJ
authors.lastname: Brown
authors.forename: M W
authors.initials: MW
authors.lastname: Reed
authors.forename: C A
authors.initials: CA
authors.lastname: Staton
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007150:Immunohistochemistry; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D013925:Thromboplastin / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D013925:Thromboplastin