Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease

Br J Cancer. 2009 Aug 18;101(4):666-72. doi: 10.1038/sj.bjc.6605196. Epub 2009 Jul 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / analysis
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Carcinoma, Ductal, Breast / metabolism
  • Carcinoma, Ductal, Breast / pathology
  • Carcinoma, Intraductal, Noninfiltrating / metabolism
  • Carcinoma, Intraductal, Noninfiltrating / pathology
  • Cell Proliferation
  • Endothelial Cells / metabolism
  • Female
  • Humans
  • Hyperplasia / pathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
  • Immunohistochemistry
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology*
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / pathology*
  • Prognosis
  • Thromboplastin / biosynthesis
  • Vascular Endothelial Growth Factor A / biosynthesis


  • Biomarkers, Tumor
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Vascular Endothelial Growth Factor A
  • Thromboplastin