title: VDR status arbitrates the prometastatic effects of tumor-associated macrophages.
abstract: The relationship between tumor-associated macrophages (TAM) and epithelial-to-mesenchymal transition (EMT) during the initiation and progression of metastasis is still unclear. Here, a role for the vitamin D receptor (VDR) in metastasis was identified, as well as a role in the relationship between TAMs and EMT. First, the expression level of VDR was examined in clinical tissue from human patients with breast cancer or a mouse model of breast cancer with differential metastasis. These results revealed that VDR expression negatively correlates with metastasis in breast cancer. Second, coculture of VDR-overexpressing breast cancer cells with a macrophage cell line demonstrated that overexpression of VDR alleviated the prometastatic effect of cocultured macrophages on breast cancer cells. Furthermore, VDR overexpression abrogated the induction of EMT in breast cancer cells by cocultured macrophage cells, as measured by a loss of E-cadherin (CDH1) and induction of α-smooth muscle actin (α-SMA). TNFα in macrophage conditioned media inhibited VDR expression, whereas downregulation of VDR further mediated the promotion of TGFβ-induced EMT by TNFα. In addition, β-catenin expression was inhibited in VDR-overexpressing breast cancer cells and tumor xenografts. Finally, administration of calcitriol [1,25-(OH)2D3], an active vitamin D metabolite, exerted similar antimetastatic effects in breast cancer cells in vitro and a mouse model of breast cancer in vivo with preservation of VDR and suppression of β-catenin.
  
  
  CONCLUSIONS
  VDR suppression by TNFα mediates the prometastatic effect of TAMs through enhancement of the β-catenin pathway.
authors.affiliation: Departments of Immunology and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Departments of Immunology and.
authors.forename: Quanjun
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Pathology, Medical School of Nankai University, Tianjin; and.
authors.forename: Zhujun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Departments of Immunology and.
authors.forename: Nan
authors.initials: N
authors.lastname: Bai
authors.affiliation: Departments of Immunology and.
authors.forename: Ze
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Pathology, Medical School of Nankai University, Tianjin; and.
authors.forename: Min
authors.initials: M
authors.lastname: Xiong
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Departments of Immunology and xiaoyuetan@nankai.edu.cn rxiang@nankai.edu.cn.
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.affiliation: Pathology, Medical School of Nankai University, Tianjin; and xiaoyuetan@nankai.edu.cn rxiang@nankai.edu.cn.
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Tan
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000473:pathology*; D018167:Receptors, Calcitriol / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000199:Actins; D015820:Cadherins; D018167:Receptors, Calcitriol; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin