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.