title: DACT1, an antagonist to Wnt/β-catenin signaling, suppresses tumor cell growth and is frequently silenced in breast cancer.
abstract: BACKGROUND
  Aberrant activation of Wnt/β-catenin signaling plays an important role in the pathogenesis of breast cancer. DACT1 (Dapper/Frodo) has been identified as involved in antagonizing Wnt/β-catenin signaling through interacting with Dishevelled (Dvl), a central mediator of Wnt signaling, whereas its role in breast tumorigenesis remains unclear.
  
  
  METHODS
  We examined DACT1 expression in breast cancer cell lines and primary tumors with semiquantitative or quantitative RT-PCR and immunochemistry, and further evaluated the promoter methylation of DACT1 with methylation-specific PCR (MSP). We also explored the tumor-suppressive functions of DACT1 in vivo and in vitro, and its related mechanism in breast cancer.
  
  
  RESULTS
  We identified DACT1 as a methylated target in our breast cancer epigenome study. Here, we further investigated DACT1 expression in multiple breast cell lines and primary tumors, and further studied its function and molecular mechanisms. We found that DACT1 expression was silenced in eight (88.9%) of nine breast cancer cell lines, and its protein levels were obviously reduced in breast tumors compared with paired surgical-margin tissues. Promoter CpG methylation of DACT1 was detected in five (55.6%) of nine breast cancer cell lines and 40 (29.9%) of 134 primary tumors, but not in surgical-margin tissues and normal breast tissues. Demethylation treatment of breast cancer cell lines restored DACT1 expression along with promoter demethylation, suggesting that an epigenetic mechanism mediates DACT1 silencing in breast cancer. Functional assays showed that ectopic expression of DACT1 could inhibit breast tumor cell proliferation in vivo and in vitro through inducing apoptosis, and further suppress tumor cell migration through antagonizing the Wnt/β-catenin signaling pathway.
  
  
  CONCLUSIONS
  Our study demonstrates that DACT1 could function as a tumor suppressor but was frequently downregulated in breast cancer.
authors.forename: Xuedong
authors.initials: X
authors.lastname: Yin
authors.forename: Tingxiu
authors.initials: T
authors.lastname: Xiang
authors.forename: LiLi
authors.initials: L
authors.lastname: Li
authors.forename: Xianwei
authors.initials: X
authors.lastname: Su
authors.forename: Xingsheng
authors.initials: X
authors.lastname: Shu
authors.forename: Xinrong
authors.initials: X
authors.lastname: Luo
authors.forename: Jianbo
authors.initials: J
authors.lastname: Huang
authors.forename: Ying
authors.initials: Y
authors.lastname: Yuan
authors.forename: Weiyan
authors.initials: W
authors.lastname: Peng
authors.forename: Michael
authors.initials: M
authors.lastname: Oberst
authors.forename: Kathleen
authors.initials: K
authors.lastname: Kelly
authors.forename: Guosheng
authors.initials: G
authors.lastname: Ren
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation; D019175:DNA Methylation; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D060449:Wnt Signaling Pathway; D014945:Wound Healing; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491683:DACT1 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger