Overexpression of angiotensin II type 1 receptor in breast cancer cells induces epithelial-mesenchymal transition and promotes tumor growth and angiogenesis

Eunhye Oh, Ji Young Kim, Youngkwan Cho, Hyunsook An, Nahyun Lee, Hunho Jo, Changill Ban, Jae Hong Seo

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1071-1081
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1863
Issue number6
DOIs
Publication statusPublished - 2016 Jun 1

Fingerprint

Angiotensin Type 1 Receptor
Epithelial-Mesenchymal Transition
Breast Neoplasms
Growth
Neoplasms
Losartan
Cell Proliferation
Angiotensin I
Angiotensin Receptors
Poly(ADP-ribose) Polymerases
Extracellular Signal-Regulated MAP Kinases
MCF-7 Cells
Snails
Metalloproteases
Cadherins
Microvessels
Heterografts
Homeostasis
Up-Regulation
Apoptosis

Keywords

  • AGTR1
  • Angiogenesis
  • Breast cancer
  • EMT
  • Losartan
  • Smad4

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Overexpression of angiotensin II type 1 receptor in breast cancer cells induces epithelial-mesenchymal transition and promotes tumor growth and angiogenesis. / Oh, Eunhye; Kim, Ji Young; Cho, Youngkwan; An, Hyunsook; Lee, Nahyun; Jo, Hunho; Ban, Changill; Seo, Jae Hong.

In: Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1863, No. 6, 01.06.2016, p. 1071-1081.

Research output: Contribution to journalArticle

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