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Hypomethylation of the Synuclein Gene CpG Island Promotes Its Aberrant Expression in Breast Carcinoma and Ovarian Carcinoma¹

Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304 [A. G., A. L., J. L.], and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [A. K. G., L.V.]

Recent studies indicate that synuclein (SNCG) gene, located in chromosome 10, participates in the pathogenesis of the breast and ovary. SNCG, also known as breast cancer-specific gene 1 (BCSG1), is not expressed in normal mammary or ovarian surface epithelial cells but is highly expressed in the vast majority of advanced staged breast and ovarian carcinomas. When overexpressed, SNCG significantly stimulates breast cancer proliferation and metastasis. To fully understand the molecular mechanisms underlying the abnormal expression of SNCG in neoplastic diseases, in this study, we extensively examined the methylation status of a CpG island located in exon 1 of SNCG gene in a panel of breast and ovarian tumor-derived cell lines to determine whether DNA methylation plays a crucial role in SNCG expression. In vivo bisulfite DNA sequencing of genomic DNA isolated from breast cancer cell lines showed that the 15 CpG sites within the CpG island were completely unmethylated in all SNCG-positive cell lines (5 of 5), but were densely and heterogeneously methylated in the majority of SNCG-negative cell lines (3 of 4). The methylation occurred primarily at the CpG sites 2, 5, 7, and 10–15. Similarly, we observed a strong correlation of hypomethylation of the CpG island and SNCG expression in ovarian cancer cell lines (5 of 5). Intriguingly, the methylation pattern in ovarian cancer cells is different from that in breast cancer cells. In SNCG-nonexpressing ovarian cancer cells, all 15 of the CpG sites were completely methylated instead of selective methylation at certain sites shown in breast cancer cells, thereby suggesting a tissue-specific methylation pattern. A correlation between hypomethylation of the exon 1 and expression of SNCG mRNA was also observed in primary breast tumor tissues. The importance of DNA methylation in the control of SNCG expression in cancer cells is further strengthened by demonstration of re-expression of SNCG mRNA in SNCG-negative ovarian and breast cancer cells with a demethylating agent 5-aza-2'-deoxycytidine. In addition, we demonstrate that inhibition of cell growth leads to a decreased mRNA expression and an increased DNA methylation of SNCG gene. Taken together, these new findings strongly suggest that DNA hypomethylation is a common mechanism underlying the abnormal expression of this candidate oncogene in breast and ovarian carcinomas.

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