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

Objective. This study examined the potential role of Angiotensin 11 for the regulation of angiogenesis associated genes in receptor positive and negative human breast cancer. Methods. Expression of different Renin-Angiotensin system (R-AS) components in human breast cancer tissue was investigated using immunofluorescence, and in a receptor positive (MCF-7) and receptor negative (NIDA-MB 468) breast cancer cell line by perfortning immunocytochemistry and RT-PCR. Both cell lines were stimulated with Angiotensin 11 and Angiotensin 11 receptor type I (At, R) blocker Candesartan, and geneexpression of vascular endothelial growth factor(VEGF), Angiopoietin I and 2 (Ang-1 and Ang-2), tissue inhibitor of matrix metalloprotemases I (TIMP-1), and hypoxia inducible transcription factor 2 alpha (HIF-2 alpha) were quantified by TaqMan-Real-Time PCR analysis. Results. RAS components, Angiotensinogen, Renin, Angiotensin I-converting enzyme (ACE), and At1R and At2R were expressed in homonereceptor 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, TIMPA,-1 and HIF-2 alpha in both cell lines. However, only in receptor negative MDA-MB 468 cells, did Angiotensin II significantly increase gene expression of VEGF, HIF-2 alpha, and TIMP-1 This effect was completely inhibited by Candesartan. Conclusion. In conclusion, it is hypothesized that Angiotensin 11 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. (c) 2008 Elsevier Inc. All rights reserved.