title: Antagonists of IGF:Vitronectin Interactions Inhibit IGF-I-Induced Breast Cancer Cell Functions.
abstract: We provide proof-of-concept evidence for a new class of therapeutics that target growth factor:extracellular matrix (GF:ECM) interactions for the management of breast cancer. Insulin-like growth factor-I (IGF-I) forms multiprotein complexes with IGF-binding proteins (IGFBP) and the ECM protein vitronectin (VN), and stimulates the survival, migration and invasion of breast cancer cells. For the first time we provide physical evidence for IGFBP-3:VN interactions in breast cancer patient tissues; these interactions were predominantly localized to tumor cell clusters and in stroma surrounding tumor cells. We show that disruption of IGF-I:IGFBP:VN complexes with L(27)-IGF-II inhibits IGF-I:IGFBP:VN-stimulated breast cancer cell migration and proliferation in two- and three-dimensional assay systems. Peptide arrays screened to identify regions critical for the IGFBP-3/-5:VN and IGF-II:VN interactions demonstrated IGFBP-3/-5 and IGF-II binds VN through the hemopexin-2 domain, and VN binds IGFBP-3 at residues not involved in the binding of IGF-I to IGFBP-3. IGFBP-interacting VN peptides identified from these peptide arrays disrupted the IGF-I:IGFBP:VN complex, impeded the growth of primary tumor-like spheroids and, more importantly, inhibited the invasion of metastatic breast cancer cells in 3D assay systems. These studies provide first-in-field evidence for the utility of small peptides in antagonizing GF:ECM-mediated biologic functions and present data demonstrating the potential of these peptide antagonists as novel therapeutics. Mol Cancer Ther; 15(7); 1602-13. ©2016 AACR.
authors.affiliation: Queensland University of Technology, Tissue Repair and Regeneration Program, Institute of Health and Biomedical Innovation, Brisbane, Queensland, Australia. Cancer Immunology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland. abhishek.kashyap@unibas.ch b.hollier@qut.edu.au.
authors.forename: Abhishek S
authors.initials: AS
authors.lastname: Kashyap
authors.affiliation: Queensland University of Technology, Tissue Repair and Regeneration Program, Institute of Health and Biomedical Innovation, Brisbane, Queensland, Australia.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Shooter
authors.affiliation: Queensland University of Technology, Tissue Repair and Regeneration Program, Institute of Health and Biomedical Innovation, Brisbane, Queensland, Australia.
authors.forename: Ali
authors.initials: A
authors.lastname: Shokoohmand
authors.affiliation: Queensland University of Technology, Tissue Repair and Regeneration Program, Institute of Health and Biomedical Innovation, Brisbane, Queensland, Australia.
authors.forename: Jacqui
authors.initials: J
authors.lastname: McGovern
authors.affiliation: Roche Innovation Center, Pharma Research and Early Development, Basel, Switzerland.
authors.forename: Manaswini
authors.initials: M
authors.lastname: Sivaramakrishnan
authors.affiliation: Queensland University of Technology, Tissue Repair and Regeneration Program, Institute of Health and Biomedical Innovation, Brisbane, Queensland, Australia.
authors.forename: Tristan I
authors.initials: TI
authors.lastname: Croll
authors.affiliation: Department of Immunology, Genetics and Pathology Science for Life Laboratory, BMC, Uppsala University, Uppsala, Sweden.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Cane
authors.affiliation: Queensland University of Technology, Tissue Repair and Regeneration Program, Institute of Health and Biomedical Innovation, Brisbane, Queensland, Australia.
authors.forename: David I
authors.initials: DI
authors.lastname: Leavesley
authors.affiliation: Department of Immunology, Genetics and Pathology Science for Life Laboratory, BMC, Uppsala University, Uppsala, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Söderberg
authors.affiliation: Queensland University of Technology, Tissue Repair and Regeneration Program, Institute of Health and Biomedical Innovation, Brisbane, Queensland, Australia.
authors.forename: Zee
authors.initials: Z
authors.lastname: Upton
authors.affiliation: Queensland University of Technology, Tissue Repair and Regeneration Program, Institute of Health and Biomedical Innovation, Brisbane, Queensland, Australia. Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Translational Research Institute, Brisbane, Queensland, Australia. abhishek.kashyap@unibas.ch b.hollier@qut.edu.au.
authors.forename: Brett G
authors.initials: BG
authors.lastname: Hollier
mesh_terms: D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000737:chemistry / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D013002:Somatomedins / Q000737:chemistry / Q000378:metabolism*; D019096:Vitronectin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D008024:Ligands; D046912:Multiprotein Complexes; D010446:Peptide Fragments; D013002:Somatomedins; D019096:Vitronectin; D007334:Insulin-Like Growth Factor I