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Overexpression of angiotensin II type 1 receptor in breast cancer cells induces epithelial-mesenchymal transition and promotes tumor growth and angiogenesis
- Source :
- Biochimica et biophysica acta. 1863(6 Pt)
- Publication Year :
- 2015
-
Abstract
- The angiotensin II type I receptor (AGTR1) has been implicated in diverse aspects of human disease, from the regulation of blood pressure and cardiovascular homeostasis to cancer progression. We sought to investigate the role of AGTR1 in cell proliferation, epithelial-mesenchymal transition (EMT), migration, invasion, angiogenesis and tumor growth in the breast cancer cell line MCF7. Stable overexpression of AGTR1 was associated with accelerated cell proliferation, concomitant with increased expression of survival factors including poly(ADP-ribose) polymerase (PARP) and X-linked inhibitor of apoptosis (XIAP), as well as extracellular signal-regulated kinase (ERK) activation. AGTR1-overexpressing MCF7 cells were more aggressive than their parent line, with significantly increased activity in migration and invasion assays. These observations were associated with changes in EMT markers, including reduced E-cadherin expression and increased p-Smad3, Smad4 and Snail levels. Treatment with the AGTR1 antagonist losartan attenuated these effects. AGTR1 overexpression also accelerated tumor growth and increased Ki-67 expression in a xenograft model. This was associated with increased tumor angiogenesis, as evidenced by a significant increase in microvessels in the intratumoral and peritumoral areas, and enhanced tumor invasion, with the latter response associated with increased EMT marker expression and matrix metallopeptidase 9 (MMP-9) upregulation. In vivo administration of losartan significantly reduced both tumor growth and angiogenesis. Our findings suggest that AGTR1 plays a significant role in tumor aggressiveness, and its inhibition may have therapeutic implications.
- Subjects :
- 0301 basic medicine
Epithelial-Mesenchymal Transition
Angiogenesis
Blotting, Western
Transplantation, Heterologous
Mice, Nude
Breast Neoplasms
Biology
Inhibitor of apoptosis
Losartan
Receptor, Angiotensin, Type 1
03 medical and health sciences
0302 clinical medicine
medicine
Animals
Humans
Epithelial–mesenchymal transition
Molecular Biology
Cell Proliferation
Smad4 Protein
Mice, Inbred BALB C
Microscopy, Confocal
Neovascularization, Pathologic
Cell growth
Reverse Transcriptase Polymerase Chain Reaction
Cancer
Cell Biology
medicine.disease
Cadherins
Angiotensin II
Molecular biology
XIAP
Tumor Burden
Gene Expression Regulation, Neoplastic
030104 developmental biology
Matrix Metalloproteinase 9
030220 oncology & carcinogenesis
Cancer research
MCF-7 Cells
Female
Poly(ADP-ribose) Polymerases
Angiotensin II Type 1 Receptor Blockers
medicine.drug
Subjects
Details
- ISSN :
- 00063002
- Volume :
- 1863
- Issue :
- 6 Pt
- Database :
- OpenAIRE
- Journal :
- Biochimica et biophysica acta
- Accession number :
- edsair.doi.dedup.....4eefa51bdaad5b4ea324b47f3c5be26f