No conflicts of interest were declared.
Epigenetic inactivation of microRNA gene hsa-mir-9-1 in human breast cancer†
Article first published online: 18 OCT 2007
Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 214, Issue 1, pages 17–24, January 2008
How to Cite
Lehmann, U., Hasemeier, B., Christgen, M., Müller, M., Römermann, D., Länger, F. and Kreipe, H. (2008), Epigenetic inactivation of microRNA gene hsa-mir-9-1 in human breast cancer. J. Pathol., 214: 17–24. doi: 10.1002/path.2251
- Issue published online: 7 DEC 2007
- Article first published online: 18 OCT 2007
- Manuscript Accepted: 26 AUG 2007
- Manuscript Revised: 23 AUG 2007
- Manuscript Received: 18 APR 2007
- Deutsche Krebshilfe. Grant Number: 10-1842-Le I
- Deutsche Forschungsgemeinschaft. Grant Number: KFo 119/2
- microRNA genes;
- DNA methylation;
- breast cancer;
MicroRNAs (miRNAs) represent a new class of small non-coding RNAs regulating gene expression by inducing RNA degradation or interfering with translation. Aberrant miRNA expression has been described for several human malignancies and tumour suppressor functions have been ascribed to this new class of small regulatory RNAs. Accordingly, inactivation due to deletion or mutation has been found in human malignancies. Here, we describe the role of aberrant hypermethylation as an additional mechanism for miRNA gene inactivation in human breast cancer. Aberrant hypermethylation was shown for mir-9-1, mir-124a3, mir-148, mir-152, and mir-663 in 34–86% of cases in a series of 71 primary human breast cancer specimens. For comprehensive methylation analysis, combined bisulphite restriction analysis, bisulphite sequencing, and Pyrosequencing™ were employed. miRNA gene hypermethylation correlated strongly with methylation of known tumour suppressor genes (p = 0.003). After treatment of various breast cancer cell lines with the demethylating agent 5-aza-2′-deoxycytidine, reduction of mir-9-1 gene methylation and concomitant reactivation of expression could be observed. For the mir-9-1 gene, which is already hypermethylated in pre-invasive intraductal lesions, a good correlation between quantitative methylation level and reduction of expression could be demonstrated in a subset of primary human breast cancer specimen (r = 0.8). In conclusion, this study demonstrates that various microRNA genes are also affected by epigenetic inactivation due to aberrant hypermethylation and that this is an early and frequent event in breast cancer development. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.