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.
Highlights
Cell-intrinsic defenses against invading pathogens are a relatively new discovery [1]
In our previous expression profiling study of 14 novel primary breast cancer cell lines of varying histological grade developed in our laboratory, and 51 breast epithelial cell lines established by others [16], bone marrow stromal antigen 2 (BST2) was among the most highly expressed genes in grade 3 tumor lines identified by Significance Analysis of Microarrays (SAM)
We have established functional phenotypes resulting from differential BST2 expression by using breast cancer cell lines of varying grade
Summary
Cell-intrinsic defenses against invading pathogens are a relatively new discovery [1]. To assist the host’s immune system in controlling microbial spread during productive infection, these defenses function as ‘restriction factors’. Among these factors, the bone marrow stromal antigen 2 (BST2)/tetherin is known to dramatically reduce the release of the human immunodeficiency virus, as well as a range of other viruses from infected cells [2,3] by directly tethering virions to cells [4]. In blood derived human immune cells, BST2 activation and type I interferon (IFN) production appear to share the same triggers ensuring that BST2 expression, and its role in the IFN negative feedback loop are synchronized [6]. BST2 is normally detected in dendritic cells, terminally differentiated B cells, and bone marrow stromal cells [10], and is overexpressed in some hematological cancers [11]
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