Abstract 2509: Blockage of angiotensin II type 1 receptor (AGTR1) inhibits epithelial-mesenchymal transition (EMT) and tumor growth in breast cancer

Abstract

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. A recent study has reported pathogenic overexpression of the angiotensin II type 1 receptor (AGTR1) in breast cancers. We sought to investigate the effect of losartan, an angiotensin II receptor blocker on cell proliferation, epithelial-mesenchymal transition (EMT), angiogenesis and tumor growth in breast cancer. 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 in vitro. To confirm the physiological relevance of our in vitro observations, we examined the effect of losartan on tumor growth using a mammary fat pad xenograft model with the AGTR1-overexpressing cells. Losartan administration resulted in a significant reduction in tumor growth and a significant decrease in the number of Ki-67-positive cells in the AGTR1-overexpressing xenograft tumors. Losartan administration notably upregulated E-cadherin and suppressed vimentin expression. Furthermore, microvessel density analysis revealed that the number of CD31-positive microvessels in both the peritumoral and intratumoral areas was significantly decreased in the losartan-treated groups. Our findings support the notion that AGTR1 is a potentially useful diagnostic marker and its inhibition may provide an effective therapeutic strategy for breast cancer treatment. Citation Format: Ji Young Kim, Eunhye Oh, Yoon-Jae Kim, Daeil Sung, Tae-Min Cho, Seojin Jang, Jae Hong Seo. Blockage of angiotensin II type 1 receptor (AGTR1) inhibits epithelial-mesenchymal transition (EMT) and tumor growth in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2509.