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

¹ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland; ² Lovelace Respiratory Research Institute, Albuquerque, New Mexico; ³ Cancer Epigenetics Laboratory, Spanish National Cancer Centre, Madrid, Spain; ⁴ Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland; ⁵ Division of Hematology/Oncology, Northwestern University Medical School, Chicago, Illinois; and Departments of ⁶ Craniofacial Biology and ⁷ Cell and Structural Biology, University of Colorado Health Sciences Center, Denver, Colorado

The transcription factor activator protein-2 (AP-2) 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-2 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-2, 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-2 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-2 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-2 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.

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