Research Papers:

Epigenetic silencing of NKD2, a major component of Wnt signaling, promotes breast cancer growth

Yan Dong _, Baoping Cao, Meiying Zhang, Weidong Han, James G. Herman, François Fuks, Yali Zhao and Mingzhou Guo

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Oncotarget. 2015; 6:22126-22138. https://doi.org/10.18632/oncotarget.4244

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Yan Dong1,2, Baoping Cao1,3, Meiying Zhang1,3, Weidong Han2, James G. Herman4, François Fuks5, Yali Zhao6, Mingzhou Guo1

1Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing 100853, China

2Department of Molecular Biology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing 100853, China

3Medical College of NanKai University, Tianjin 300071, China

4The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, U.S.A

5Laboratory of Cancer Epigenetics, Free University of Brussels (U.L.B.), 808 route de Lennik, Brussels 1070, Belgium

6Central Laboratory, The Affiliated Hainan Hospital of Chinese PLA General Hospital, Hai Tang Wan, Sanya 572013, China

Correspondence to:

Mingzhou Guo, e-mail: [email protected]

Yali Zhao, e-mail: [email protected]

Keywords: NKD2, DNA methylation, Wnt signaling, epigenetics, breast cancer

Received: February 27, 2015     Accepted: June 08, 2015     Published: June 19, 2015


Naked cuticle homolog 2 (NKD2) has been reported to antagonize Wnt signaling in zebrafish, mouse and mammals. The aim of this study is to investigate the epigenetic changes and mechanisms of NKD2 in human breast cancer development. Six breast cancer cell lines (MCF-7, ZR75–1, MDA-MB-468, MDA-MB-231, T47D and BT474) and 68 cases of primary human breast cancer were studied using methylation specific PCR, immunohistochemistry, western blot, flow cytometry techniques and a xenograft mouse model. The expression of NKD1 and NKD2 was regulated by promoter region methylation in breast cancer cells. No NKD1 methylation was found in primary human breast cancer. NKD2 was methylated in 51.4% (35/68) of human primary breast cancer samples. NKD2 methylation was significantly associated with reduction of NKD2 expression, and tumor stage (p < 0.05). NKD2 suppressed breast cancer cell proliferation both in vitro and in vivo. NKD2 induced G1/S arrest and inhibited Wnt signaling in breast cancer cells. In conclusion, NKD2 is frequently methylated in human breast cancer, and the expression of NKD2 is regulated by promoter region methylation. NKD2 suppresses breast cancer proliferation by inhibiting Wnt signaling.

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