title: WISP3 (CCN6) is a secreted tumor-suppressor protein that modulates IGF signaling in inflammatory breast cancer.
abstract: Inflammatory breast cancer (IBC) is the most lethal form of locally advanced breast cancer. We have found that WISP3 is lost in 80% of human IBC tumors and that it has growth- and angiogenesis-inhibitory functions in breast cancer in vitro and in vivo. WISP3 is a cysteine-rich, putatively secreted protein that belongs to the CCN family. It contains a signal peptide at the N-terminus and four highly conserved motifs. Here, for the first time, we investigate the function of WISP3 protein in relationship to its structural features. We found that WISP3 is secreted into the conditioned media and into the lumens of normal breast ducts. Once secreted, WISP3 was able to decrease, directly or through induction of other molecule(s), the IGF-1-induced activation of the IGF-IR, and two of its main downstream signaling molecules, IRS1 and ERK-1/2, in SUM149 IBC cells. Furthermore, WISP3 containing conditioned media decreased the growth rate of SUM149 cells. This work sheds light into the mechanism of WISP3 function by demonstrating that it is secreted and that, once in the extracellular media, it induces a series of molecular events that leads to modulation of IGF-IR signaling pathways and cellular growth in IBC cells.
authors.affiliation: Department of Pathology, Division of Hematology and Oncology, University of Michigan Medical Center, Ann Arbor, MI 48108, USA.
authors.forename: Celina G
authors.initials: CG
authors.lastname: Kleer
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Quintin
authors.initials: Q
authors.lastname: Pan
authors.forename: Sofia D
authors.initials: SD
authors.lastname: Merajver
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D055511:CCN Intercellular Signaling Proteins; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D007249:Inflammation; D055504:Insulin Receptor Substrate Proteins; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D055511:CCN Intercellular Signaling Proteins; C400081:CCN6 protein, human; D017077:Culture Media, Conditioned; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D025521:Tumor Suppressor Proteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases