title: DNA methylation of heparanase promoter influences its expression and associated with the progression of human breast cancer.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Binzhou Medical College, Yantai, Shandong Province, People's Republic of China.
authors.forename: Fei
authors.initials: F
authors.lastname: Jiao
authors.affiliation: Department of Clinical Laboratory, Tai'an City Central Hospital, Tai'an, Shandong Province, People's Republic of China.
authors.forename: Shi-Yu
authors.initials: SY
authors.lastname: Bai
authors.affiliation: Department of Biochemistry and Molecular Biology, Binzhou Medical College, Yantai, Shandong Province, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Medicine, Columbia University, New York, New York, United States of America.
authors.forename: Zhong-Hai
authors.initials: ZH
authors.lastname: Yan
authors.affiliation: Department of Biochemistry and Molecular Biology, Binzhou Medical College, Yantai, Shandong Province, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yue
authors.affiliation: Department of Biochemistry and Molecular Biology, Binzhou Medical College, Yantai, Shandong Province, People's Republic of China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Clinical Laboratory, the PLA 107th Hospital Affiliated to Binzhou Medical College Yantai, Shandong Province, Jinan Military Area Command, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biotechnology, Binzhou Medical College, Yantai, Shandong Province, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000235:genetics*; D006801:Humans; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000235:genetics*; D000099175:Heparanase
chemical_list: D001374:Azacitidine; D000077209:Decitabine; D005966:Glucuronidase; D000099175:Heparanase