title: Quercetin inhibits angiogenesis by targeting calcineurin in the xenograft model of human breast cancer.
abstract: 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, 5.6mg/kg), tacrolimus (FK506, 3mg/kg), or Qu (34mg/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.
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China.
authors.forename: Qiuting
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China.
authors.forename: Shijun
authors.initials: S
authors.lastname: Yang
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China.
authors.forename: Xiaoya
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China. Electronic address: zmzou@implad.ac.cn.
authors.forename: Zhongmei
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China. Electronic address: dycai@implad.ac.cn.
authors.forename: Dayong
authors.initials: D
authors.lastname: Cai
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D019703:Calcineurin / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced; D021381:Protein Transport / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D043925:Angiogenesis Inducing Agents; D000970:Antineoplastic Agents; D050778:NFATC Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C445503:transcription factor NF-AT c3; D011794:Quercetin; D040301:Vascular Endothelial Growth Factor Receptor-2; D019703:Calcineurin
keywords: Angiogenesis; Breast cancer; Calcineurin; Quercetin