Insulin-like growth factor-I

Vitronectin complex-induced changes in gene expression effect breast cell survival and migration

Abhishek S. Kashyap, Brett G. Hollier, Kerry J. Manton, K. Satyamoorthy, David I. Leavesley, Zee Upton

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Recent studies have demonstrated that IGF-I associates with vitronectin (VN) through IGF-binding proteins (IGFBP), which in turn modulate IGF-stimulated biological functions such as cell proliferation, attachment, and migration. Because IGFs play important roles in transformation and progression of breast tumors, we aimed to describe the effects of IGF-I:IGFBP:VN complexes on breast cell function and to dissect mechanisms underlying these responses. In this study we demonstrate that substrate-bound IGF-I:IGFBP:VN complexes are potent stimulators of MCF-7 breast cell survival, which is mediated by a transient activation of ERK/MAPK and sustained activation of phosphoinositide 3-kinase/AKT pathways. Furthermore, use of pharmacological inhibitors of the MAPK and phosphoinositide 3-kinase pathways confirms that both path ways are involved in IGF-I:IGFBP:VN complex-mediated increased cell survival. Microarray analysis of cells stimulated to migrate in response to IGF-I:IGFBP:VN complexes identified differential expression of genes with previously reported roles in migration, invasion, and survival (Ephrin-B2, Sharp-2, Tissue-factor, Stratifin, PAI-1, IRS-1). These changes were not detected when the IGF-I analogue ([L24][A31]-IGF-I), which fails to bind to the IGF-I receptor, was substituted; confirming the IGF-I-dependent differential expression of genes associated with enhanced cell migration. Taken together, these studies have established that IGF-I:IGFBP:VN complexes enhance breast cell migration and survival, processes central to facilitating metastasis. This study highlights the interdependence of extracellular matrix and growth factor interactions in biological functions critical for metastasis and identifies potential novel therapeutic targets directed at preventing breast cancer progression.

Original languageEnglish
Pages (from-to)1388-1401
Number of pages14
JournalEndocrinology
Volume152
Issue number4
DOIs
Publication statusPublished - 04-2011

Fingerprint

Vitronectin
Insulin-Like Growth Factor I
Cell Movement
Insulin-Like Growth Factor Binding Proteins
Cell Survival
Breast
Gene Expression
1-Phosphatidylinositol 4-Kinase
Ephrin-B2
Tissue Array Analysis
Breast Neoplasms
Neoplasm Metastasis
IGF Type 1 Receptor
Plasminogen Activator Inhibitor 1
MCF-7 Cells
Thromboplastin
Extracellular Matrix
Intercellular Signaling Peptides and Proteins
Cell Proliferation
Pharmacology

All Science Journal Classification (ASJC) codes

  • Endocrinology

Cite this

Kashyap, Abhishek S. ; Hollier, Brett G. ; Manton, Kerry J. ; Satyamoorthy, K. ; Leavesley, David I. ; Upton, Zee. / Insulin-like growth factor-I : Vitronectin complex-induced changes in gene expression effect breast cell survival and migration. In: Endocrinology. 2011 ; Vol. 152, No. 4. pp. 1388-1401.
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abstract = "Recent studies have demonstrated that IGF-I associates with vitronectin (VN) through IGF-binding proteins (IGFBP), which in turn modulate IGF-stimulated biological functions such as cell proliferation, attachment, and migration. Because IGFs play important roles in transformation and progression of breast tumors, we aimed to describe the effects of IGF-I:IGFBP:VN complexes on breast cell function and to dissect mechanisms underlying these responses. In this study we demonstrate that substrate-bound IGF-I:IGFBP:VN complexes are potent stimulators of MCF-7 breast cell survival, which is mediated by a transient activation of ERK/MAPK and sustained activation of phosphoinositide 3-kinase/AKT pathways. Furthermore, use of pharmacological inhibitors of the MAPK and phosphoinositide 3-kinase pathways confirms that both path ways are involved in IGF-I:IGFBP:VN complex-mediated increased cell survival. Microarray analysis of cells stimulated to migrate in response to IGF-I:IGFBP:VN complexes identified differential expression of genes with previously reported roles in migration, invasion, and survival (Ephrin-B2, Sharp-2, Tissue-factor, Stratifin, PAI-1, IRS-1). These changes were not detected when the IGF-I analogue ([L24][A31]-IGF-I), which fails to bind to the IGF-I receptor, was substituted; confirming the IGF-I-dependent differential expression of genes associated with enhanced cell migration. Taken together, these studies have established that IGF-I:IGFBP:VN complexes enhance breast cell migration and survival, processes central to facilitating metastasis. This study highlights the interdependence of extracellular matrix and growth factor interactions in biological functions critical for metastasis and identifies potential novel therapeutic targets directed at preventing breast cancer progression.",
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Insulin-like growth factor-I : Vitronectin complex-induced changes in gene expression effect breast cell survival and migration. / Kashyap, Abhishek S.; Hollier, Brett G.; Manton, Kerry J.; Satyamoorthy, K.; Leavesley, David I.; Upton, Zee.

In: Endocrinology, Vol. 152, No. 4, 04.2011, p. 1388-1401.

Research output: Contribution to journalArticle

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AU - Kashyap, Abhishek S.

AU - Hollier, Brett G.

AU - Manton, Kerry J.

AU - Satyamoorthy, K.

AU - Leavesley, David I.

AU - Upton, Zee

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