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-1a), 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 (Po0.005), and between in situ and invasive carcinomas (Po0.0005). In addition, significant increases in proliferating ECs were observed in benign hyperplastic breast compared with normal breast (Po0.05) cancers and in invasive compared with in situ cancers (Po0.005). Hypoxia-inducible factor-1a, VEGF and TF expression were significantly associated with increases in both angiogenesis and proliferating ECs (Po0.05). Moreover, HIF-1a was expressed by 60 -75% of the hyperplastic lesions, and a significant association was observed between VEGF and TF in ECs (Po0.005) and invasive tumour cells (Po0.01). CONCLUSIONS: These findings are the first to suggest that the angiogenic switch, associated with increases in HIF-1a, 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.

Anti-tissue factor short hairpin RNA inhibits breast cancer growth in vivo

“…In breast cancer, TF is associated with metastatic potential and poor prognosis [4] in addition to playing a role in angiogenesis [2]. The current study demonstrates that TF is highly expressed in metastatic breast carcinoma cells (MDA-MB-436), in contrast to non- In conclusion, these data suggest for the first time that modulation of TF has a direct effect on established primary breast cancer growth and angiogenesis that is distinct from the role in VEGF production.…”

“…Elevated TF expression in breast cancer has been associated with disease progression, poor survival, increased VEGF expression and angiogenesis [2,4]. VEGF is known to up-regulate the expression of TF in cancer cells and associated endothelial cells, potentially creating a feedback loop whereby TF in turn up-regulates VEGF expression [1].…”

“…Indeed, up-regulation of TF protein by cancer cells and associated stromal cells has been well documented in breast cancer and other malignant tumours [2][3][4].…”

“…TF levels have been correlated with advanced stages of malignancy and metastatic potential in different cancers, including breast [2,4], suggesting that TF may play a role in tumour progression, which may be related to the putative role of TF in metastatic disease as TF inhibition reduces both melanoma and breast cancer cell metastasis in vivo [5,6].…”

“…TF also up-regulates the pro-angiogenic protein, vascular endothelial growth factor (VEGF) [8], the most potent known stimulator of angiogenesis, and correlates with both microvessel density (MVD; a surrogate marker of angiogenesis) and VEGF expression in breast and colon cancer [2,3].…”