title: Cysteine-linked dimerization of BST-2 confers anoikis resistance to breast cancer cells by negating proapoptotic activities to promote tumor cell survival and growth.
abstract: Almost all breast tumors express the antiviral protein BST-2 with 67%, 25% and 8.2% containing high, medium or low levels of BST-2, respectively. Breast tumor cells and tissues that contain elevated levels of BST-2 are highly aggressive. Suppression of BST-2 expression reprograms tumorigenic properties of cancer cells and diminishes cancer cell aggressiveness. Using structure/function studies, we report that dimerization of BST-2 through cysteine residues located in the BST-2 extracellular domain (ECD), leads to anoikis resistance and cell survival through proteasome-mediated degradation of BIM-a key proapoptotic factor. Importantly, BST-2 dimerization promotes tumor growth in preclinical breast cancer models in vitro and in vivo. Furthermore, we demonstrate that restoration of the ECD cysteine residues is sufficient to rescue cell survival and tumor growth via a previously unreported pathway-BST-2/GRB2/ERK/BIM/Cas3. These findings suggest that disruption of BST-2 dimerization offers a potential therapeutic approach for breast cancer.
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Wadie D
authors.initials: WD
authors.lastname: Mahauad-Fernandez
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.|Interdisciplinary Graduate Program in Molecular and Cellular Biology (MCB), University of Iowa, Iowa City, IA, USA.
authors.forename: Chioma M
authors.initials: CM
authors.lastname: Okeoma
mesh_terms: D000818:Animals; D023102:Anoikis / Q000502:physiology*; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D003545:Cysteine / Q000378:metabolism*; D019281:Dimerization; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D003545:Cysteine; D058851:GPI-Linked Proteins; D051380:GRB2 Adaptor Protein; D008565:Membrane Proteins; D046988:Proteasome Endopeptidase Complex; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2