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Sox17, the canonical Wnt antagonist, is epigenetically inactivated by promoter methylation in human breast cancer

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Abstract

SRY-box 17 (Sox17) is a transcription factor which involved in a variety of developmental processes and can act as an antagonist of canonical Wnt/β-catenin signaling pathway. However, the relationship between Sox17 gene expression, methylation status, and β-catenin in breast cancer has not been established. Here we report that the expression level of Sox17 mRNA was dramatically decreased in five different breast cancer cell lines and 23 of 31 primary breast tumor samples, which significantly correlated with its methylation status. After treated with 5-aza-2′-deoxycytidine (5-aza-dC, a demethylation agent), the expression levels of Sox17 mRNA and protein were obviously increased. Restored expression of Sox17 by 5-aza-dC treatment decreased the expression level of β-catenin in breast cancer cell lines. Furthermore, small interfering RNA (siRNA)-mediated knockdown of Sox17 in SKBR-3 and Bacp-37 cells enhanced β-catenin expression. In 31 paired tissue samples, a significant difference between the expression level of Sox17 and β-catenin was also observed (P < 0.001). Clinically, Sox17 methylation was detected in 74.3% breast tumors (84/113) and 31.9% (36/113) paired normal tissues, respectively (P < 0.0001). Sox17 methylation was also associated with tumor stage (P = 0.028) and lymph node metastasis (P = 0.013). These findings indicate that silencing of Sox17 due to promoter hypermethylation is a frequent event and may contribute to aberrant activation of Wnt signaling in breast cancer. Sox17 may be a valuable biomarker for the study of breast cancer carcinogenesis and progression.

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Acknowledgments

The authors thank the studied patients for their willingness to cooperate with our study. This research was supported in part by the grants from the National Basic Research Program of China (2006CB910501, 2004CB518605), National Natural Science Foundation of China (30371580, 30572109); Chinese National Natural Science Fund for Distinguished Young Scholars (30625019); Shanghai Science and Technology Committee (03J14019, 06DJ14004, 06DZ19504).

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Authors and Affiliations

  1. Department of Breast Surgery, Cancer Hospital/Cancer Institute, Breast Cancer Institute, Fudan University, 399 Ling-Ling Road, Shanghai, 200032, China

    De-Yuan Fu,  Li-Chen, Zhen-Zhou Shen & Zhi-Ming Shao

  2. Chinese National Human Genome Center at Shanghai, 250 Bi Bo Road, Shanghai, 201203, China

    Zhi-Min Wang, Bei-Lan Wang & Wei Huang

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  1. De-Yuan Fu
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  2. Zhi-Min Wang
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Correspondence to Wei Huang or Zhi-Ming Shao.

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De-Yuan Fu and Zhi-Min Wang have contributed equally to this work.

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Fu, DY., Wang, ZM., Li-Chen et al. Sox17, the canonical Wnt antagonist, is epigenetically inactivated by promoter methylation in human breast cancer. Breast Cancer Res Treat 119, 601–612 (2010). https://doi.org/10.1007/s10549-009-0339-8

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