Potential role of Renin–Angiotensin-system for tumor angiogenesis in receptor negative breast cancer

ObjectiveThis study examined the potential role of Angiotensin II for the regulation of angiogenesis associated genes in receptor positive and negative human breast cancer.MethodsExpression of different Renin–Angiotensin system (RAS) components in human breast cancer tissue was investigated using immunofluorescence, and in a receptor positive (MCF-7) and receptor negative (MDA-MB 468) breast cancer cell line by performing immunocytochemistry and RT-PCR. Both cell lines were stimulated with Angiotensin II and Angiotensin II receptor type 1 (At1R) blocker Candesartan, and gene expression of vascular endothelial growth factor (VEGF), Angiopoietin 1 and 2 (Ang-1 and Ang-2), tissue inhibitor of matrix metalloproteinases 1 (TIMP-1), and hypoxia inducible transcription factor 2α (HIF-2α) were quantified by TaqMan-Real-Time PCR analysis.ResultsRAS components, Angiotensinogen, Renin, Angiotensin I-converting enzyme (ACE), and At1R and At2R were expressed in hormone-receptor negative and positive human breast cancer tissue as well as in MDA-MB 468 and in MCF-7 human breast cancer cells. In addition, we found expression of VEGF, Ang-1, TIMP-1, and HIF-2α in both cell lines. However, only in receptor negative MDA-MB 468 cells, did Angiotensin II significantly increase gene expression of VEGF, HIF-2α, and TIMP-1. This effect was completely inhibited by Candesartan.ConclusionIn conclusion, it is hypothesized that Angiotensin II may be involved in regulation of tumor angiogenesis especially in receptor negative breast cancer by regulation of angiogenesis associated genes via At1R. These findings are the first evidence for targeting tumor angiogenesis by inhibition of At1R in receptor negative human breast cancer cells and may lead to new therapeutical anticancer strategies based upon inhibition of At1R.