Promoter methylation-associated loss of ID4 expression is a marker of tumour recurrence in human breast cancer
The aim of this study was to reveal the factual role of the Inhibitor of DNA binding/Inhibitor of differentiation 4 (ID4) in carcinogenesis in more detail, since its role for the pathogenesis of human breast cancer has been discussed controversially, assigning both oncogenic and tumour suppressive functions.
Methods: ID4 promoter methylation, ID4 mRNA expression and ID4 protein expression were analysed in primary human breast cancer specimens using methylation-specific PCR (MSP) (n=170), semiquantitative realtime RT-PCR (n=46) and immunhistochemistry (n=3), respectively. In order to demonstrate a functional association of ID4 promoter methylation with its gene silencing, we performed DNA demethylation analysis with four human breast cell lines using MSP and semiquantitative realtime RT-PCR.
In addition, we performed correlations of ID4 promoter methylation with ID4 mRNA and ID4 protein expression in matched samples of breast tumour and corresponding normal tissue. We carried out statistical analyses in order to find correlations between ID4 promoter methylation and clinicopathological parameters.
Results: Frequent ID4 promoter methylation was observed in primary breast cancer samples (69%, 117/170).
We found a tight correlation (P<0.0001) between ID4 promoter methylation and loss of ID4 expression in primary breast cancer specimens. Demethylating treatment with breast cancer cell lines was associated with clear ID4 mRNA re-expression.
Tumours with ID4 promoter methylation showed distinct loss of ID4 expression on both transcription and protein level. Interestingly, ID4 promoter methylation was a factor for unfavourable recurrence-free survival (P=0.036) and increased risk for lymph node metastasis (P=0.030).
Conclusions: ID4 is indeed a novel tumour suppressor gene in normal human breast tissue and is epigenetically silenced during cancer development, indicating increased risk for tumour relapse.
Thus, ID4 methylation status could serve as a prognostic biomarker in human breast cancer.
Author: Erik Noetzel, Juergen Veeck, Dieter Niederacher, Oliver Galm, Felicitas Horn, Arndt Hartmann, Ruth Knuechel and Edgar Dahl
Credits/Source: BMC Cancer 2008, 8:154
Published on: 2008-05-30
Copyright by the authors listed above - made available via BioMedCentral (Open Access). Please
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