Hypermethylation of a Small CpGuanine-Rich Region Correlates with Loss of Activator Protein-2α Expression during Progression of Breast Cancer

Donna B. Douglas, Yoshimitsu Akiyama, Hetty Carraway, Steven A. Belinsky, Manel Esteller, Edward Gabrielson, Sigmund Weitzman, Trevor Williams, James G. Herman, Stephen B. Baylin

Research output: Contribution to journalArticlepeer-review

Abstract

The transcription factor activator protein-2α (AP-2α) has recently been implicated as a tumor suppressor protein that can be lost during tumor progression and that exhibits growth-inhibitory properties when overexpressed in cancer cell lines. We now demonstrate that hypermethylation of a discrete 5′ region within a promoter CpG island of the gene is associated in breast cancer with the loss of AP-2α expression. Multiple CpG sites within the island become hypermethylated during breast cancer evolution. However, only hypermethylation of the most CpG-rich region, a small, ∼300-bp area at the 3′ end of exon 1, fully distinguishes neoplastic from normal breast tissue and correlates with transcriptional silencing. In cell culture, silenced AP-2α, associated with exon 1 hypermethylation, is re-expressed by 5-aza-2′deoxycytidine resulting in the restoration of a functional DNA sequence-specific binding protein. In vivo, as detected by a very sensitive nested PCR approach, methylation of the discrete AP-2α exon 1 region does not occur in normal breast epithelium and occurs in only 3 (16%) of 19 ductal carcinoma in situ (DCIS) lesions, but is present in 12 (75%) of 16 invasive breast tumors (P < 0.001; DCIS versus invasive cancers). Tumors unmethylated for this region expressed AP-2α protein throughout, whereas tumors with hypermethylation showed large areas of loss. Our studies then determine that hypermethylation of a small region of a CpG island correlates with silencing of AP-2α in breast cancer and suggest that inactivation of this gene could be a factor in, and a useful marker for, the progression of DCIS lesions.

Original languageEnglish (US)
Pages (from-to)1611-1620
Number of pages10
JournalCancer Research
Volume64
Issue number5
DOIs
StatePublished - Mar 1 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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