Quercetin inhibits angiogenesis by targeting calcineurin in the xenograft model of human breast cancer

Vascular endothelial growth factor receptor 2 (VEGFR2) mediated calcineurin/nuclear factor of activated T-cells (NFAT) pathway is crucial in the angiogenesis of human breast cancer. Quercetin (Qu), a flavonoid known to possess anti-angiogenesis and antitumor properties, inhibited calcineurin activity in vitro. Herein, we performed a study in vivo to evaluate the effects of Qu on the angiogenesis in breast cancer. Female BALB/c nude mice were injected with MCF-7 cells into the mammary fat and were randomly divided into four groups. The animals were treated with vehicle solution, tamoxifen (TAM, 5.6 mg/kg), tacrolimus (FK506, 3 mg/kg), or Qu (34 mg/kg) for 21 days, respectively. The results showed that, similar to TAM and FK506, Qu decreased tumor growth, limited oncocyte proliferation and promoted tumor necrosis. Anti-angiogenic actions of Qu were demonstrated as decreased serum VEGF (P< 0.01), and sparse microvessel density (P < 0.05). Qu significantly inhibited tumor calcineurin activities, and the inhibitory rate was 62.73% in Qu treated animals, compared to that was 72.90% in FK506 group (P > 0.05). Effects of Qu on calcineurin/NFAT pathway were confirmed as decreased subcellular located levels of VEGF (P < 0.05), VEGFR2 (P < 0.05) and NFATc3 (P< 0.01), downregulated gene expression of VEGF (P< 0.05), VEGFR2 (P< 0.05) and NFATc3 (P< 0.01), reduced protein levels of VEGF (P< 0.05), VEGFR2 (P < 0.05), and NFATc3 (P < 0.01) in tumor tissues. These findings indicate that Qu inhibit angiogenesis of human breast cancer xenograft in nude mice, which was associated with suppressing calcineurin activity and its regulated pathway activation. (C) 2016 Elsevier B.V. All rights reserved.