Sox17, the canonical Wnt antagonist, is epigenetically inactivated by promoter methylation in human breast cancer.
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/beta-catenin signaling pathway. However, the relationship between Sox17 gene expression, methylation status, and beta-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 beta-catenin in breast cancer cell lines. Furthermore, small interfering RNA (siRNA)-mediated knockdown of Sox17 in SKBR-3 and Bacp-37 cells enhanced beta-catenin expression. In 31 paired tissue samples, a significant difference between the expression level of Sox17 and beta-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.
Fu
De-Yuan
DY
Department of Breast Surgery, Cancer Hospital/Cancer Institute, Breast Cancer Institute, Fudan University, 399 Ling-Ling Road, Shanghai 200032, China.
Wang
Zhi-Min
ZM
Li-Chen
Wang
Bei-Lan
BL
Shen
Zhen-Zhou
ZZ
Huang
Wei
W
Shao
Zhi-Ming
ZM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055760:SOXF Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C109188:SOX17 protein, human; D055760:SOXF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin