Hypermethylation leads to silencing of the SYK gene in human breast cancer

A number of cancer-associated genes have been shown to be inactivated by hy permethylation of CpG islands during breast tumorigenesis. SYK, a candidate tumor suppressor, has been found not expressed in a subset of breast cance r cell lines, but the mechanism by which SYK is silenced is unclear, In thi s study, we examined the 5 ' CpG island methylation status of the SYK gene in breast cancer cell lines and primary breast cancer tissues. We found SYK 5 ' CpG hypermethylation in 30% (6/20) of breast cancer cell lines, and th e aberrant methylation status was strongly associated with loss of SYK gene expression. Treatment of cells with a methylation inhibitor, 5-aza-2 ' -de oxycytidine, led to a reactivation of SYK expression in SYK-negative cells, as detected by reverse transcription-PCR, Using methylation-specific PCR, we demonstrated that SYK is hypermethylated in 32% (12/37) of unselected br east tumors, whereas all of the matched neighboring normal breast tissues e xhibited unmethylated DNA status, We concluded that SYK is frequently inact ivated through an epigenetic pathway in breast cancer. Because SYK: has bee n shown to function as a tumor suppressor, and its loss of expression in br east cancer has been correlated with tumor invasiveness, the aberrant SYK m ethylation is responsible for the loss of expression and may consequently p lay a permissive role for tumor aggressiveness.