title: 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.
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California, USA.
authors.forename: Aejaz
authors.initials: A
authors.lastname: Sayeed
authors.forename: Gloria
authors.initials: G
authors.lastname: Luciani-Torres
authors.forename: Zhenhang
authors.initials: Z
authors.lastname: Meng
authors.forename: James L
authors.initials: JL
authors.lastname: Bennington
authors.forename: Dan H
authors.initials: DH
authors.lastname: Moore
authors.forename: Shanaz H
authors.initials: SH
authors.lastname: Dairkee
mesh_terms: D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004357:Drug Synergism; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D011485:Protein Binding; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000502:physiology; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D015703:Antigens, CD; D018931:Antineoplastic Agents, Hormonal; D050556:Fatty Acid-Binding Proteins; D058851:GPI-Linked Proteins; D000077185:Resveratrol; D013267:Stilbenes; D013629:Tamoxifen; D016212:Transforming Growth Factor beta; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C493410:FABP4 protein, human