Carcinogenesis Advance Access originally published online on March 19, 2008
Carcinogenesis 2008 29(5):991-998; doi:10.1093/carcin/bgn076
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Epigenetic inactivation of the secreted frizzled-related protein-5 (SFRP5) gene in human breast cancer is associated with unfavorable prognosis
Molecular Oncology Group, Institute of Pathology, University Hospital of the RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
1 Department of Pathology, University of Erlangen, 91054 Erlangen, Germany
* To whom correspondence should be addressed. Tel: +49 241 8088431; Fax: +49 241 8082439; Email: edahl{at}ukaachen.de
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.
Abbreviations: CI, confidence interval; DAC, 5-aza-2'-deoxycytidine; DFS, disease-free survival; EGF, epidermal growth factor; FC, fold change; GSK3-β, glycogen synthase kinase 3-β; GAPDH, glyceraldehyde-3-phosphate-dehydrogenase; HR, hazard ratio; mRNA, messenger RNA; MSP, methylation-specific polymerase chain reaction; OS, overall survival; PCR, polymerase chain reaction; SFRP, secreted frizzled-related protein; TCF/LEF, T-cell factor/lymphocyte enchancer factor; TSA, trichostatin A
These authors contributed equally to this work. Received January 14, 2008; revised February 22, 2008; accepted March 11, 2008.
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