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.

The angiotensin receptor blocker, Losartan, inhibits mammary tumor development and progression to invasive carcinoma

“…Interestingly, angiotensin II-mediated stimulation significantly increased VEGFA gene expression only in ER −ve cell lines, which was completely inhibited by the ARB, Candesartan [38]. A recently published study also confirms a pro-tumourigenic role of AT 1 R demonstrating that overexpression of AT 1 R in an ER +ve breast cancer cell line resulted in increased proliferation, increased expression of poly(ADP-ribose) polymerase (PARP) and X-linked inhibitor of apoptosis (XIAP), increased ERK, p-Smad3/4 activation [39]. Furthermore, treatment with Losartan attenuated these effects.…”

“…Furthermore, treatment with Losartan attenuated these effects. Overexpression of AT 1 R also accelerated tumor growth, increased tumor angiogenesis, enhanced tumor invasiveness as demonstrated by increased expression of EMT markers including matrix metallopeptidase 9 (MMP-9) and reduced E-cadherin [39]. Collectively these studies identify the mechanisms via which AT 1 R facilitates tumor growth and invasiveness in breast cancer.…”

Aberrant expression of lncRNAs and mRNAs in patients with intracranial aneurysm

“…It reported that AGTR1 could regulate blood pressure and promote angiogenesis [26]. MYLK can encode smooth muscle and nonmuscle isoforms.…”

Flubendazole elicits anti‐metastatic effects in triple‐negative breast cancer via STAT3 inhibition

“…The procedures were performed as previously described . The primary antibody dilutions were [phospho‐Histone H3 (Ser10, 1:2000), β‐tubulin (1:2000), STAT3 (1:2000) phospho‐STAT3 (Tyr705, 1:2000), PARP (1:2000), cleaved‐PARP (1:2000), cleaved‐caspase 3 (1:1000), cleaved‐caspase 7 (1:1000), CD49f (1:2000), ALDH1A1 (1:2000), cyclin D1 (1:2000), survivin (1:2000) and actin (1:5000)] and membranes were incubated with HRP‐conjugated rabbit or mouse secondary antibodies (1:3000–1:10,000).…”