AGTR1 promotes lymph node metastasis in breast cancer by upregulating CXCR4/SDF-1α and inducing cell migration and invasion

The angiotensin II type I receptor (AGTR1) has a strong influence on tumor growth, angiogenesis, inflammation and immunity. However, the role of AGTR1 on lymph node metastasis (LNM) in breast cancer, which correlates with tumor progression and patient survival, has not been examined. AGTR1 was highly expressed in lymph node-positive tumor tissues, which was confirmed by the Oncomine database. Next, inhibition of AGTR1 reduced tumor growth and LNM in orthotopic xenografts by bioluminescence imaging (BLI). Losartan, an AGTR1-specific inhibitor, decreased the chemokine pair CXCR4/SDF-1 alpha levels in vivo and inhibited AGTR1-induced cell migration and invasion in vitro. Finally, the molecular mechanism of AGTR1-induced cell migration and LNM was assessed by knocking down AGTR1 in normal cells or CXCR4 in AGTR1(high )cells. AGTR1-silenced cells treated with losartan showed lower CXCR4 expression. AGTR1 overexpression caused the upregulation of FAK/RhoA signaling molecules, while knocking down CXCR4 in AGTR1(high) cells downregulated these molecules. Collectively, AGTR1 promotes LNM by increasing the chemokine pair CXCR4/SDF-1 alpha and tumor cell migration and invasion. The potential mechanism of AGTR1-mediated cell movement relies on activating the FAK/RhoA pathway. Our study indicated that inhibiting AGTR1 may be a potential therapeutic target for LNM in early-stage breast cancer.