Role of DNA Methyltransferase in the Progression of Breast Cancer to a Hormone Independent Phenotype

摘要

Approximately a quarter of breast cancer patients lack estrogen receptor (ER) expression and respond poorly to hormonal treatment. Absence of ER expression is associated with lack of transcript, methylation of the CpG island in the promoter region of this gene, and increased DNMT activity. This study addresses the hypothesis that specific inhibition of DNMT1 by antisense oligonucleotides (DNMTl ASO) is sufficient to re-express ER in ER- human breast cancer cell lines. Significant growth reduction was observed in two ER- cell lines after 48 hr exposure to DNMTl ASO. DMTl expression was blocked as detected by Western whereas mutated DNMTl ASO had no effect. Transcriptional re- expression of ER as well as other methylation-silenced genes such as PR cyclin D2 and retinoic acid receptor (3) was observed. ER protein expression was observed after ASO treatment. However, methylation specific PCR indicated that ER promoter CpG islands were onl6y partially demethylated. Our results suggest that specific DNMTl inhibition alone is sufficient to re-express ER in human breast cancer cell line. This might be an alternative anti-cancer strategy for ER- human breast cancer.