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Hypermethylation Leads to Silencing of the SYK Gene in Human Breast Cancer¹

Departments of Molecular Pathology [Y. Y., R. M., J. L. D.] and Pathology [A. S.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

A number of cancer-associated genes have been shown to be inactivated by hypermethylation of CpG islands during breast tumorigenesis. SYK, a candidate tumor suppressor, has been found not expressed in a subset of breast cancer cell lines, but the mechanism by which SYK is silenced is unclear. In this 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 the aberrant methylation status was strongly associated with loss of SYK gene expression. Treatment of cells with a methylation inhibitor, 5-aza-2'-deoxycytidine, 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 breast tumors, whereas all of the matched neighboring normal breast tissues exhibited unmethylated DNA status. We concluded that SYK is frequently inactivated through an epigenetic pathway in breast cancer. Because SYK has been shown to function as a tumor suppressor, and its loss of expression in breast cancer has been correlated with tumor invasiveness, the aberrant SYK methylation is responsible for the loss of expression and may consequently play a permissive role for tumor aggressiveness.

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