Potential role of Renin-Angiotensin-system for tumor angiogenesis in receptor negative breast cancer.
OBJECTIVE
This study examined the potential role of Angiotensin II for the regulation of angiogenesis associated genes in receptor positive and negative human breast cancer.


METHODS
Expression 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 (At(1)R) 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 2alpha (HIF-2alpha) were quantified by TaqMan-Real-Time PCR analysis.


RESULTS
RAS components, Angiotensinogen, Renin, Angiotensin I-converting enzyme (ACE), and At(1)R and At(2)R 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-2alpha in both cell lines. However, only in receptor negative MDA-MB 468 cells, did Angiotensin II significantly increase gene expression of VEGF, HIF-2alpha, and TIMP-1. This effect was completely inhibited by Candesartan.


CONCLUSIONS
In 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 At(1)R. These findings are the first evidence for targeting tumor angiogenesis by inhibition of At(1)R in receptor negative human breast cancer cells and may lead to new therapeutical anticancer strategies based upon inhibition of At(1)R.
Herr
D
D
Department of Obstetrics and Gynecology, Ulm University Medical Center, Prittwitzstrasse 43, 89075 Ulm, Germany.
Rodewald
M
M
Fraser
H M
HM
Hack
G
G
Konrad
R
R
Kreienberg
R
R
Wulff
C
C
D042683:Angiopoietin-1 / Q000096:biosynthesis / Q000235:genetics; D042702:Angiopoietin-2 / Q000096:biosynthesis / Q000235:genetics; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000096:biosynthesis; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D051792:Basic Helix-Loop-Helix Proteins; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D011960:Receptors, Estrogen; D013777:Tetrazoles; D019715:Tissue Inhibitor of Metalloproteinase-1; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C467630:ANGPT1 protein, human; C081643:candesartan