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Open Access Research article

DACT1, an antagonist to Wnt/β-catenin signaling, suppresses tumor cell growth and is frequently silenced in breast cancer

Xuedong Yin1, Tingxiu Xiang1, LiLi Li2, Xianwei Su2, Xingsheng Shu2, Xinrong Luo1, Jianbo Huang1, Ying Yuan1, Weiyan Peng1, Michael Oberst3, Kathleen Kelly3, Guosheng Ren1* and Qian Tao124*

Author Affiliations

1 Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing 400016, China

2 Cancer Epigenetics Laboratory, Department of Clinical Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Shatin, NT, Hong Kong

3 Signal Transduction Section, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA

4 Cancer Center, Dalian Medical University, 9 Lvshun Road South, Dalian 116044, China

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Breast Cancer Research 2013, 15:R23  doi:10.1186/bcr3399

Published: 12 March 2013

Abstract

Introduction

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.