title: Overexpression of angiotensin II type 1 receptor in breast cancer cells induces epithelial-mesenchymal transition and promotes tumor growth and angiogenesis.
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.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 136-705, Republic of Korea; Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea.
authors.forename: Eunhye
authors.initials: E
authors.lastname: Oh
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 136-705, Republic of Korea; Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 136-705, Republic of Korea; Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea.
authors.forename: Youngkwan
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 136-705, Republic of Korea; Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea.
authors.forename: Hyunsook
authors.initials: H
authors.lastname: An
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 136-705, Republic of Korea; Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea.
authors.forename: Nahyun
authors.initials: N
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Pohang University of Science and Technology, 77, Cheongam-Ro, Nam-Gu, Pohang, Gyeongbuk 790-784, Republic of Korea.
authors.forename: Hunho
authors.initials: H
authors.lastname: Jo
authors.affiliation: Department of Chemistry, Pohang University of Science and Technology, 77, Cheongam-Ro, Nam-Gu, Pohang, Gyeongbuk 790-784, Republic of Korea.
authors.forename: Changill
authors.initials: C
authors.lastname: Ban
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 136-705, Republic of Korea; Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea. Electronic address: cancer@korea.ac.kr.
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seo
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D019808:Losartan / Q000494:pharmacology; D061986:MCF-7 Cells; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D015820:Cadherins; D044140:Receptor, Angiotensin, Type 1; D051901:Smad4 Protein; D011065:Poly(ADP-ribose) Polymerases; D020780:Matrix Metalloproteinase 9; D019808:Losartan
keywords: AGTR1; Angiogenesis; Breast cancer; EMT; Losartan; Smad4