Aberrant Regulation of the BST2 (Tetherin) Promoter Enhances Cell Proliferation and Apoptosis Evasion in High Grade Breast Cancer Cells

Abstract

Normal cellular phenotypes that serve an oncogenic function during tumorigenesis are potential candidates for cancer targeting drugs. Within a subset of invasive primary breast carcinoma, we observed relatively abundant expression of Tetherin, a cell surface protein encoded by the Bone Marrow Stromal Cell Antigen (BST2) known to play an inhibitory role in viral release from infected immune cells of the host. Using breast cancer cell lines derived from low and intermediate histopathologic grade invasive primary tumors that maintain growth-suppressive TGFβ signaling, we demonstrate that BST2 is negatively regulated by the TGFβ axis in epithelial cells. Binding of the transcription factor AP2 to the BST2 promoter was attenuated by inhibition of the TGFβ pathway thereby increasing BST2 expression in tumor cells. In contrast, inherent TGFβ resistance characteristic of high grade breast tumors is a key factor underlying compromised BST2 regulation, and consequently its constitutive overexpression relative to non-malignant breast epithelium, and to most low and intermediate grade cancer cells. In both 2-dimensional and 3-dimensional growth conditions, BST2-silenced tumor cells displayed an enhancement in tamoxifen or staurosporine-induced apoptotic cell death together with a reduction in the S-phase fraction compared to BST2 overexpressing counterparts. In a subset of breast cancer patients treated with pro apoptotic hormonal therapy, BST2 expression correlated with a trend for poor clinical outcome, further supporting its role in conferring an anti apoptotic phenotype. Similar to the effects of gene manipulation, declining levels of endogenous BST2 induced by the phytoalexin – resveratrol, restored apoptotic function, and curbed cell proliferation. We provide evidence for a direct approach that diminishes aberrant BST2 expression in cancer cells as an early targeting strategy to assist in surmounting resistance to pro apoptotic therapies.

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

“…Despite the contradictory effects of BST-2 in various cancers in vitro, Sayeed et. al., showed that elevated BST-2 expression renders high grade breast cancer cells resistant to pro-apoptotic drug (tamoxifen and staurosporine) treatment [123]. These data point to a functional role of BST-2 in breast cancer both in the promotion/progression of breast cancer and its resistance to treatments.…”

“…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).…”

“…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].…”

Two E-selectin ligands, BST-2 and LGALS3BP, predict metastasis and poor survival of ER-negative breast cancer

“…Cai et al also reported BST-2 protein expression to be associated with breast cancer bone metastasis in a smaller cohort (n=50) of breast samples (22). Experimental data, based on cell lines and in vivo models, have hinted that BST-2 was involved in increased proliferation and reduced apoptosis (23), as well as increased migration, invasion and metastasis (21,22,24). The data we are presenting imply that the role of BST-2 in metastasis is specific to patients with ER-negative tumours, and may be further enhanced by sLe x expression.…”

Elucidation of the genetic and epigenetic landscape alterations in RNA binding proteins in glioblastoma

“…Certainly, in our analysis, we found RBPs that were already reported to contribute to the aggressiveness of the high grade cancers. These included IGF2BP3 [34, 54], S100A4 [59, 60], METTL1 [51], NPM1 [61, 62], BST2 [63], and EIF4E2 [64]. We also validated the role of two upregulated and aggressiveness related RBPs (METTL1 and OAS1) in chemoresistance of LN229 glioma cells to temozolomide.…”