Recent studies on the role of two opposite axes of angiotensinogen metabolism - ACE (angiotensin-converting enzyme)/ANGII/AT1R (angiotensin receptor type 1) and ACE-2/ANG 1-7/MAS (mitochondrial assembly) - indicate their importance in tumor growth and invasion, but studies describing the metabolic pathways in breast cancer and the role of newer angiotensins, such as ANG 1-12, remain lacking.
ANG-1, ANG-2 and VEGF levels in co-culture media and mRNA expression were upregulated and Tie2 mRNA expression was downregulated in the HUVECs and MCF-7.
There was a negative correlation between miR-153 and ANG1 levels in breast cancer. miR-153 blocked the expression and secretion of ANG1 in breast cancer cells through binding to ANG1 mRNA.
By crossing Angiopoietin-1 knockout mice to the MMTV-PyMT autochthonous mouse breast cancer model, we investigated primary tumor growth and metastasis to the lung.
GTPCH/Ang-1 interaction in stromal fibroblasts and activation of Tie2 on breast tumor cells could play an important role in supporting breast cancer growth.
In summary, our results demonstrate that downregulation of ACE2/Ang-(1-7)/Mas axis stimulates breast cancer metastasis through the activation of SOCE and PAK1/NF-κB/Snail1 pathways.
Moreover, MDA-MB-231/HMEC-1 co-cultures produced significantly increased levels of ANG2 (up to 580 pg/ml) and VEGF protein (up to 38,400 pg/ml) while ANG1 protein expression was decreased relative to MDA-MB-231 monocultures.
Overall, these results indicate that Ang-1 mRNA and protein expressions: (1) negatively correlate with the level of ERα in breast cancer cell lines; (2) are downregulated by E2 in an ERα dependent manner; and (3) positively correlate with the degree of angiogenesis in vivo.
Ang1 was then overexpressed in a human breast cancer cell line (MCF-7) on its own and in conjunction with FGF1, an angiogenic factor shown to be able to increase the tumorigenicity of MCF-7 cells.