title: Surface Expression of TGFβ Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer.
abstract: GARP encoded by the Lrrc32 gene is the cell surface docking receptor for latent TGFβ, which is expressed naturally by platelets and regulatory T cells (Treg). Although Lrrc32 is amplified frequently in breast cancer, the expression and relevant functions of GARP in cancer have not been explored. Here, we report that GARP exerts oncogenic effects, promoting immune tolerance by enriching and activating latent TGFβ in the tumor microenvironment. We found that human breast, lung, and colon cancers expressed GARP aberrantly. In genetic studies in normal mammary gland epithelial and carcinoma cells, GARP expression increased TGFβ bioactivity and promoted malignant transformation in immunodeficient mice. In breast carcinoma-bearing mice that were immunocompetent, GARP overexpression promoted Foxp3+Treg activity, which in turn contributed to enhancing cancer progression and metastasis. Notably, administration of a GARP-specific mAb limited metastasis in an orthotopic model of human breast cancer. Overall, these results define the oncogenic effects of the GARP-TGFβ axis in the tumor microenvironment and suggest mechanisms that might be exploited for diagnostic and therapeutic purposes. Cancer Res; 76(24); 7106-17. ©2016 AACR.
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Metelli
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Bill X
authors.initials: BX
authors.lastname: Wu
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Caroline W
authors.initials: CW
authors.lastname: Fugle
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Saleh
authors.initials: S
authors.lastname: Rachidi
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Shaoli
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Howe
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Bei
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. zihai@musc.edu.
authors.forename: Zihai
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D063646:Carcinogenesis; D005260:Female; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016133:Polymerase Chain Reaction; D046888:Tissue Array Analysis; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D019139:Tumor Escape / Q000502:physiology*
chemical_list: C087215:LRRC32 protein, human; D008565:Membrane Proteins; D016212:Transforming Growth Factor beta