title: Aberrant hypermethylation of ID4 gene promoter region increases risk of lymph node metastasis in T1 breast cancer.
abstract: ID4 gene is a member of the inhibitor of DNA-binding (ID) family, which inhibits DNA binding of basic helix-loop-helix transcription factors. Certain human primary breast cancers reportedly have low or no expression of ID4 protein, but its role in carcinogenesis and cancer progression is unknown. To determine its possible role, we examined epigenetic inactivation of ID4 gene by promoter hypermethylation in human breast cell lines and T1 breast cancer tissues. Methylation status of ID4 promoter CpG island was assessed by methylation-specific PCR (MSP); ID4 mRNA level was assessed by quantitative real-time RT-PCR. Of eight cell lines, two were fully methylated, four were partially methylated, and two were not methylated. ID4 mRNA level was suppressed in fully methylated cell lines. ID4 hypermethylation was observed in 16 of 24 (67%) node-positive and seven of 36 (19%) node-negative T1 primary breast cancers matched by patient age and tumor diameter. It was a significant risk factor for nodal metastasis (OR 13.1, P=0.0004). ID4 mRNA level was suppressed in hypermethylated cancer specimens (P=0.014). ID4 may play an important suppressive role in tumor progression, and its silencing by hypermethylation may increase the risk of regional lymph node metastasis.
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, CA 90404, USA.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Umetani
authors.forename: Takuji
authors.initials: T
authors.lastname: Mori
authors.forename: Kazuo
authors.initials: K
authors.lastname: Koyanagi
authors.forename: Masaru
authors.initials: M
authors.lastname: Shinozaki
authors.forename: Joseph
authors.initials: J
authors.lastname: Kim
authors.forename: Armando E
authors.initials: AE
authors.lastname: Giuliano
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D016022:Case-Control Studies; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D051796:Inhibitor of Differentiation Proteins; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D014157:Transcription Factors