- Title
- Antagonists of IGF: Vitronectin Interactions Inhibit IGF-I-Induced Breast Cancer Cell Functions
- Creator
- Kashyap, Abhishek S.; Shooter, Gary K.; Hollier, Brett G.; Shokoohmand, Ali; McGovern, Jacqui; Sivaramakrishnan, Manaswini; Croll, Tristan I.; Cane, Gaëlle; Leavesley, David I.; Söderberg, Ola; Upton, Zee
- Relation
- Molecular Cancer Therapeutics Vol. 15, Issue 7, p. 1602-1613
- Publisher Link
- http://dx.doi.org/10.1158/1535-7163.MCT-15-0907
- Publisher
- American Association for Cancer Research
- Resource Type
- journal article
- Date
- 2016
- Description
- 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 L27-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.
- Subject
- breast cancer; Insulin growth factor; vitronectin; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1446241
- Identifier
- uon:42806
- Identifier
- ISSN:1535-7163
- Language
- eng
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