Bone Marrow Stromal Antigen 2 (BST-2) DNA Is Demethylated in Breast Tumors and Breast Cancer Cells

Abstract

BackgroundBone marrow stromal antigen 2 (BST-2) is a known anti-viral gene that has been recently identified to be overexpressed in many cancers, including breast cancer. BST-2 is critical for the invasiveness of breast cancer cells and the formation of metastasis in vivo. Although the regulation of BST-2 in immune cells is unraveling, it is unknown how BST-2 expression is regulated in breast cancer. We hypothesized that meta-analyses of BST-2 gene expression and BST-2 DNA methylation profiles would illuminate mechanisms regulating elevated BST-2 expression in breast tumor tissues and cells.Materials and MethodsWe performed comprehensive meta-analyses of BST-2 gene expression and BST-2 DNA methylation in The Cancer Genome Atlas (TCGA) and various Gene Expression Omnibus (GEO) datasets. BST-2 expression levels and BST-2 DNA methylation status at specific CpG sites on the BST-2 gene were compared for various breast tumor molecular subtypes and breast cancer cell lines.ResultsWe show that BST-2 gene expression is inversely associated with the methylation status at specific CpG sites in primary breast cancer specimens and breast cancer cell lines. BST-2 demethylation is significantly more prevalent in primary tumors and cancer cells than in normal breast tissues or normal mammary epithelial cells. Demethylation of the BST-2 gene significantly correlates with its mRNA expression. These studies provide the initial evidence that significant differences exist in BST-2 DNA methylation patterns between breast tumors and normal breast tissues, and that BST-2 expression patterns in tumors and cancer cells correlate with hypomethylated BST-2 DNA.ConclusionOur study suggests that the DNA methylation pattern and expression of BST-2 may play a role in disease pathogenesis and could serve as a biomarker for the diagnosis of breast cancer.

The role of BST‐2/Tetherin in host protection and disease manifestation

“…The spectrum of BST-2 expression in various cancers has been revealed using meta analyses studies of large tumor datasets [119]. In solid tumors, BST-2 expression is elevated in head and neck cancer [120], lung cancer [121], breast cancer [119,122,123], cervical cancer [124], myelomas [125,126], endometrial cancer [127], and glioblastoma [128]. In addition, data from proteinatlas.org reveal that BST-2 is overexpressed in colorectal cancer, ovarian cancer, thyroid cancer, and pancreatic cancer (http://www.proteinatlas.org/ ENSG00000130303-BST2/cancer).…”

“…The significance of elevated BST-2 in various cancers is beginning to evolve. However, not all cancers have elevated BST-2 [119] (Table 2). Compared to normal tissues, BST-2 expression in lung adenocarcinoma and thyroid cancer is unchanged [119] whereas levels of BST-2 in lung squamous cell carcinoma, kidney papillary cell carcinoma, kidney chromophobe carcinoma, liver, and prostate cancer is significantly downregulated [119].…”

“…However, not all cancers have elevated BST-2 [119] (Table 2). Compared to normal tissues, BST-2 expression in lung adenocarcinoma and thyroid cancer is unchanged [119] whereas levels of BST-2 in lung squamous cell carcinoma, kidney papillary cell carcinoma, kidney chromophobe carcinoma, liver, and prostate cancer is significantly downregulated [119]. Thus, in some cancers, constitutive upregulation of BST-2 expression and BST-2 activity correlates with disease pathology in human and have been functionally demonstrated to cause disease in mouse models of breast cancer.…”

“…Correlation studies using meta analyses of various tumor datasets showed that BST-2 levels are proportional to the aggressiveness of different cancers including breast [123,129], brain [128], and oral cavity cancers [120]. In vitro, overexpression of BST-2 in breast cancer cells enhanced cell migration, invasion, proliferation, and anchorage-independent growth [119,123,129] whereas BST-2 suppression results in reduced migration, invasion, anchorage-independent growth but not cell proliferation [45]. In contrast to the effects of BST-2 on breast cancer cells, in HT1080 (human fibrosarcoma epithelial cell line) and MDCK (canine kidney cells) cells, overexpression of BST-2 decreased cell growth and migration due to reduced matrix metalloproteinase 2 (MMP-2) activity [130].…”

HCMV Infection Promotes the High Expression of BST-2 in Glioma Cells

“…[6,9] , cervical cancer [10] , myeloma, endometrial cancer [11] , etc., suggesting that BST-2 has a carcinogenic effect. This experiment confirmed that …”