Abstract
Abstract Propose: Accumulating evidence suggests that angiotensin II type 1 receptor (AGTR1) is involved in tumorigenesis and metastasis in many types of cancer, however little is known about its role in breast cancer. Our objective of the present study is to investigate the effect of AGTR1 overexpression on cell proliferation, epithelial-mesenchymal transition (EMT), migration, invasion, angiogenesis and tumorigenesis of human breast cancer. Methods: To determine the role of AGTR1, MCF7 cells were stably transfected with an expression construct carrying the GFP cDNA for AGTR1. MTS assay, Matrigel invasion assay, wound healing assay, Western blotting and immunofluorescence were used. For in vivo study, parental MCF7 or AGTR1-MCF7 cells were subcutaneously injected into the left and right flanks of nude mice. Tumor growth and angiogenesis were determined. Results and conclusion: AGTR1-MCF7 cells, expressing high level of AGTR1 exhibited significant increases in cell proliferation, migration and invasion capacities compared with parental MCF7 cells. Furthermore, AGTR1-MCF7 cells displayed the mesenchymal phenotype, as evidenced by elongated spindle morphology, decreased E-cadherin level, increased N-cadherin and snail, and nuclear accumulation of smad3 and smad4. Interestingly, blockade of smad4 using small interfering RNA strongly induced mesenchymal to epithelial transition (MET) and restoration of E-cadherin expression in AGTR1-MCF7 cells, suggesting that AGTR1-induced EMT is ultimately mediated by smad4 activation. Finally, we showed that AGTR1 overexpression enhanced tumor volume (p<0.001, n = 10) and weight (p<0.01) as well as increased angiogenesis in human breast cancer xenograft in vivo. In summary, we demonstrate that AGTR1 overexpression promotes cell proliferation, EMT, angiogenesis and tumorigenic properties of breast cancer cells. Our findings suggest that AGTR1 could be a useful target of therapy in breast cancer. Citation Format: Eunhye Oh, Ji Young Kim, Youngkwan Cho, Nahyun Lee, Hyunsook An, Jun Suk Kim, Jae Hong Seo. Overexpression of angiotensin II type 1 receptor induces epithelial-mesenchymal transition and promotes tumorigenesis of human breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1445. doi:10.1158/1538-7445.AM2015-1445
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