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Background  Inhibitor of DNA binding/Inhibitor of differentiation 4 ( ID4 ) is a critical factor for cell proliferation and differentiation in normal vertebrate development.  ID4  has regulative functions for differentiation and growth of the developing brain. The role of  ID1 ,  ID2  and  ID3  are expected to be oncogenic due to their overexpression in pancreatic cancer and colorectal adenocarcinomas, respectively. Aside from these findings, loss of  ID3  expression was demonstrated in ovarian cancer. The aim of the present study was to reveal the factual role of  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 3 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).Conclusion  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.

Promoter methylation-associated loss of ID4expression is a marker of tumour recurrence in human breast cancer