Epigenetic inactivation of the secreted frizzled-related protein-5 (SFRP5) gene in human breast cancer is associated with unfavorable prognosis
Epigenetic inactivation of the secreted frizzled-related protein-5 (SFRP5) gene in human breast cancer is associated with unfavorable prognosis
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DOI：
10.1093/carcin/bgn076
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发表时间：
2008-05-01
期刊：
影响因子：
4.7
通讯作者：
Dahl, Edgar
中科院分区：
文献类型：
--
作者：
Veeck, Juergen;Geisler, Cordelia;Dahl, Edgar
Wnt通路的破坏被认为在人类癌症的发展中至关重要。分泌型卷曲相关蛋白（SFRP）家族的通路抑制成员被发现在各种恶性肿瘤中由于表观遗传失活而下调。迄今为止，只有SFRP 1在人类乳腺癌中进行了研究，我们质疑其他SFRP基因是否也可能参与这种疾病的发病机制。SFRP 5在正常人体组织（n=9）中表达的初始实时聚合酶链反应分析显示，在大多数组织（包括乳腺）中表达较弱。恶性乳腺细胞系在6例中的5例中表现出进一步的SFRP 5表达缺失。一致地，在匹配的原发性乳腺肿瘤/正常乳腺组织对中，可以证实这种下调（> 5倍）（n=8/13; 62%）。我们确定启动子甲基化是SFRP 5基因沉默的主要机制，因为SFRP 5启动子甲基化与细胞系（P=0.040）和原发性肿瘤（P =0.003）中SFRP 5表达的丧失显著相关。此外，癌细胞系在用DNA去甲基化药物治疗后重新表达SFRP 5信使RNA。在168例原发性乳腺癌中，73%的人携带甲基化的SFRP 5启动子，而27%的人不受表观遗传学改变的影响。最有趣的是，SFRP 5甲基化与总生存期（OS）降低相关（P=0.045），并且在多变量考克斯比例风险模型中是影响OS的独立风险因素（风险比：4.55; 95%置信区间：1.01-20.56; P= 0.049）。总之，SFRP 5是一个目标的表观遗传失活在人类乳腺癌，支持其作为肿瘤抑制基因的作用的假设。SFRP 5甲基化可能是一种新的基于DNA的生物标志物，可能用于临床乳腺癌管理。
Disruption of the Wnt pathway is thought to be crucial in the development of human cancer. Pathway inhibitory members of the secreted frizzled-related protein (SFRP) family were found to be downregulated due to epigenetic inactivation in various malignancies. To date, only SFRP1 has been studied in human breast cancer and we questioned whether other SFRP genes may be implicated in the pathogenesis of this disease as well. An initial real-time polymerase chain reaction analysis of SFRP5 expression in normal human tissues (n=9) revealed weak expression in most tissues, including breast. Malignant mammary cell lines showed further SFRP5 expression loss in five of six cases. Consistently, in matched pairs of primary breast tumor/normal breast tissue, this downregulation (> 5-fold) could be confirmed (n=8/13; 62%). We identified promoter methylation as the predominant mechanism of SFRP5 gene silencing since SFRP5 promoter methylation correlated significantly with loss of SFRP5 expression in cell lines (P=0.040) and primary tumors (P =0.003). Moreover, cancerous cell lines re-expressed SFRP5 messenger RNA following treatment with DNA-demethylating drugs. Of 168 primary breast carcinomas, 73% harbored a methylated SFRP5 promoter, whereas 27% were unaffected by epigenetic alteration. Most interestingly, SFRP5 methylation was associated with reduced overall survival (OS) (P=0.045) and was an independent risk factor affecting OS in a multivariate Cox proportional hazard model (hazard ratio): 4.55; 95% confidence interval: 1.01-20.56; P= 0.049). In conclusion, SFRP5 is a target of epigenetic inactivation in human breast cancer, supporting the hypothesis of its role as tumor suppressor gene. SFRP5 methylation may be a novel DNA-based biomarker potentially useful in clinical breast cancer management.