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

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-1 alpha), 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-1 alpha, VEGF and TF expression were significantly associated with increases in both angiogenesis and proliferating ECs (P < 0.05). Moreover, HIF-1 alpha 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-1 alpha, 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. British Journal of Cancer (2009) 101, 666-672. doi: 10.1038/sj.bjc.6605196 www.bjcancer.com Published online 21 July 2009 (C) 2009 Cancer Research UK