Heparanase promotes
tumor invasion and
metastasis in several
malignancies including
breast cancer. However, the roles and regulation mechanisms of
heparanase during
breast cancer progression are still not fully understood. The aim of this study is to determine the differential regulation of
heparanase gene expression in specific stages of
breast cancer by DNA methylation. We detected levels of
heparanase expression and DNA methylation patterns of its promoter in
breast cancer cell lines (MCF-7 and MDA-MB-435) and clinical tissues, respectively. It has been observed that
heparanase is highly expressed in the invasive MDA-MB-435 cells with low methylation modification in the
heparanase promoter. In contrast, lower expression of
heparanase in MCF-7 cells is accompanied by higher methylation in the promoter. Treatment of MCF-7 cells with
5-aza-2'-deoxycytidine (5-aza-dC), a potent demethylating agent, results in induction of
heparanase expression and higher invasion potential in vitro and leads to an advantage of
tumor formation in vivo. In 54 tissue samples,
cancer samples at late stages (stage IV) showed the highest
heparanase expression accomplished by little DNA methylation. On the contrary, methylation prevalence is highest in normal tissue and inversely correlated with
heparanase expression. A significant correlation between DNA methylation and clinical stage was demonstrated (p = 0.012). Collectively, these results demonstrate that DNA methylation play the regulation role in
heparanase gene in different stages of
breast cancer and present a direct effect on
tumor progression.