Philipp Lachenmann: DELPHI Rationale


Walter Hohlweg Prize 2000

Dr. Martin Widschwendter

Department of Obstetrics and Gynecology
University of Innsbruck

Methylation and silencing of the retinoic acid receptor-2 gene in breast cancer

Background: A growing body of evidence supports the hypotheses that the retinoic acid receptor-2 (RAR-2) gene is a tumor suppressor gene and that the chemopreventive effects of retinoids are due to induction of RAR-2. We examined whether methylation of RAR--2 could be responsible for its silencing in cancer cells.

Methods: Eight breast cancer cell lines were treated with the demethylating agent 5-aza-2-deoxycytidine and subsequently with all-trans-retinoic acid (ATRA), and expression of the RAR-2 gene was studied by reverse transcriptionpolymerase chain reaction (RT-PCR) analysis. Sodium bisulfite genomic sequencing was used to determine the locations of 5-methylcytosines in the RAR-2 genes of three cell lines, and methylation-specific PCR was used to determine the methylation status of RAR-2 in 16 breast cancer biopsy specimens and non-neoplastic breast tissue. Results: Cell lines SK-BR-3, T-47D, ZR-75-1, and MCF7 exhibited expression of RAR-2 only after demethylation and treatment with ATRA. The first exon expressed in the RAR-_2 transcript was methylated in cell lines ZR-75-1 and SK-BR-3. Six breast cancer specimens showed methylation in the promoter-exon region of the gene. No expression of RAR-b2 was found in any grade III lesion. An inverse association between methylation and gene expression was found in all grade II lesions. The gene from non-neoplastic breast tissue was unmethylated and expressed.

Conclusion: These results and previous data suggest that methylation of the RAR-2 gene is an initial step in breast carcinogenesis and that treatment of cancer patients with demethylating agents followed by retinoic acid may offer a new therapeutic modality.



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