Promoter hypermethylation of the SFRP2 gene is a high-frequent alteration and tumor-specific epigenetic marker in human breast cancer
| Autor: | Jürgen Veeck, Edgar Jost, Arndt Hartmann, Edgar Dahl, Ruth Knüchel, Nuran Bektas, Erik Noetzel |
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| Jazyk: | angličtina |
| Předmět: |
Adult
Cancer Research Breast Neoplasms Biology lcsh:RC254-282 Cell Line Epigenesis Genetic Breast cancer medicine Biomarkers Tumor Humans Epigenetics Breast RNA Messenger Promoter Regions Genetic Gene Aged Cell Proliferation Aged 80 and over Cell growth Research Cancer Membrane Proteins DNA Methylation Middle Aged lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Gene Expression Regulation Neoplastic Survival Rate Oncology Cell culture Health DNA methylation Cancer research Biomarker (medicine) Molecular Medicine |
| Zdroj: | Molecular Cancer Molecular cancer 7(83), (2008). doi:10.1186/1476-4598-7-83 Molecular Cancer, Vol 7, Iss 1, p 83 (2008) |
| ISSN: | 1476-4598 |
| DOI: | 10.1186/1476-4598-7-83 |
| Popis: | BackgroundWe have previously reported that expression of the Wnt antagonist genesSFRP1andSFRP5is frequently silenced by promoter hypermethylation in breast cancer. SFRP2 is a further Wnt inhibitor whose expression was recently found being downregulated in various malignancies. Here we investigated whether SFRP2 is also implicated in human breast cancer, and if so whetherSFRP2promoter methylation might serve as a potential tumor biomarker.MethodsWe analyzedSFRP2mRNA expression andSFRP2promoter methylation in 10 breast cell lines, 199 primary breast carcinomas, 20 matched normal breast tissues and 17 cancer-unrelated normal breast tissues using RT-PCR, realtime PCR, methylation-specific PCR and Pyrosequencing, respectively. SFRP2 protein expression was assessed by immunohistochemistry on a tissue microarray. Proliferation assays after transfection with anSFRP2expression vector were performed with mammary MCF10A cells. Statistical evaluations were accomplished with SPSS 14.0 software.ResultsOf the cancerous breast cell lines, 7/8 (88%) lackedSFRP2mRNA expression due toSFRP2promoter methylation (P< 0.001).SFRP2expression was substantially restored in most breast cell lines after treatment with 5-aza-2'-deoxycytidine and trichostatin A. In primary breast carcinomas SFRP2 protein expression was strongly reduced in 93 of 125 specimens (74%).SFRP2promoter methylation was detected in 165/199 primary carcinomas (83%) whereas all cancer-related and unrelated normal breast tissues were not affected bySFRP2methylation.SFRP2methylation was not associated with clinicopathological factors or clinical patient outcome. However, loss of SFRP2 protein expression showed a weak association with unfavorable patient overall survival (P= 0.071). Forced expression ofSFRP2in mammary MCF10A cells substantially inhibited proliferation rates (P= 0.045).ConclusionTheSFRP2gene is a high-frequent target of epigenetic inactivation in human breast cancer. Its methylation leads to abrogation ofSFRP2expression, conferring a growth advantage to epithelial mammary cells. This altogether supports a tumor suppressive function ofSFRP2. Although clinical patient outcome was not associated withSFRP2methylation, the high frequency of this epimutation and its putative specificity to neoplastic cells may qualifySFRP2promoter methylation as a potential candidate screening marker helping to improve early breast cancer detection. |
| Databáze: | OpenAIRE |
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