Aberrant hypermethylation of ID4 gene promoter region increases risk of lymph node metastasis in T1 breast cancer

Naoyuki Umetani, Takuji Mori, Kazuo Koyanagi, Masaru Shinozaki, Joseph Kim, Armando E. Giuliano, Dave S.B. Hoon

Research output: Contribution to journalArticlepeer-review

89 Scopus citations


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). 1D4 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.

Original languageEnglish
Pages (from-to)4721-4727
Number of pages7
Issue number29
StatePublished - Jul 7 2005

Bibliographical note

Funding Information:
This study was supported in part by funding from the Susan Komen Breast Cancer Foundation, Gonda Foundation, US Army DOD Breast Grant, and FANY.


  • Breast cancer
  • Hypermethylation
  • ID4
  • Lymph node metastasis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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