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Osteopontin-induced migration of human mammary epithelial cells involves activation of EGF receptor and multiple signal transduction pathways.
Oncogene. 2003 Feb 27; 22(8):1198-205.O

Abstract

Osteopontin (OPN) is a secreted, integrin-binding glycophosphoprotein that has been implicated in breast cancer. We previously showed that OPN-induced cell migration of mammary epithelial cells (MEC) depends on binding to cell surface integrins and involves activation of the hepatocyte growth factor (HGF) receptor, Met. Here, we show that OPN-induced migration of MEC also requires activation of the epidermal growth factor (EGF) pathway. Synergism was seen between EGF and OPN in inducing cell migration. Furthermore, incubation of cells with exogenous OPN increased ligand (TGFalpha> EGF) and EGF receptor (EGFR) mRNA expression, as well as EGFR kinase activity. Treatment of cells with anti-TGFalpha or anti-EGFR antibody, or with tyrphostin-25 (EGFR inhibitor), significantly impaired the cell migration response to OPN. Other more broad-spectrum tyrosine kinase inhibitors and the growth factor/ receptor interaction inhibitor, suramin, also inhibited OPN-induced migration. Using specific signal transduction pathway inhibitors, we have screened for involvement of MEK (MAP kinase kinase), phosphatidylinositol 3-kinase, phospholipase C (PLC), and protein kinase C (PKC). Results implicated all of these pathways in OPN-induced cell migration, the most pronounced effect being seen with PLC and PKC inhibitors. These results suggest that induction of MEC migration by OPN involves a cascade of events including at least two growth factor/receptor pathways and multiple downstream signal transduction pathways. A number of potential targets are thus provided for strategies aimed at blocking the malignancy-promoting effects of OPN.

Authors+Show Affiliations

Department of Pathology, London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada. atuck@uwo.caNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

12606946

Citation

Tuck, Alan B., et al. "Osteopontin-induced Migration of Human Mammary Epithelial Cells Involves Activation of EGF Receptor and Multiple Signal Transduction Pathways." Oncogene, vol. 22, no. 8, 2003, pp. 1198-205.
Tuck AB, Hota C, Wilson SM, et al. Osteopontin-induced migration of human mammary epithelial cells involves activation of EGF receptor and multiple signal transduction pathways. Oncogene. 2003;22(8):1198-205.
Tuck, A. B., Hota, C., Wilson, S. M., & Chambers, A. F. (2003). Osteopontin-induced migration of human mammary epithelial cells involves activation of EGF receptor and multiple signal transduction pathways. Oncogene, 22(8), 1198-205.
Tuck AB, et al. Osteopontin-induced Migration of Human Mammary Epithelial Cells Involves Activation of EGF Receptor and Multiple Signal Transduction Pathways. Oncogene. 2003 Feb 27;22(8):1198-205. PubMed PMID: 12606946.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Osteopontin-induced migration of human mammary epithelial cells involves activation of EGF receptor and multiple signal transduction pathways. AU - Tuck,Alan B, AU - Hota,Charulata, AU - Wilson,Sylvia M, AU - Chambers,Ann F, PY - 2003/2/28/pubmed PY - 2003/4/4/medline PY - 2003/2/28/entrez SP - 1198 EP - 205 JF - Oncogene JO - Oncogene VL - 22 IS - 8 N2 - Osteopontin (OPN) is a secreted, integrin-binding glycophosphoprotein that has been implicated in breast cancer. We previously showed that OPN-induced cell migration of mammary epithelial cells (MEC) depends on binding to cell surface integrins and involves activation of the hepatocyte growth factor (HGF) receptor, Met. Here, we show that OPN-induced migration of MEC also requires activation of the epidermal growth factor (EGF) pathway. Synergism was seen between EGF and OPN in inducing cell migration. Furthermore, incubation of cells with exogenous OPN increased ligand (TGFalpha> EGF) and EGF receptor (EGFR) mRNA expression, as well as EGFR kinase activity. Treatment of cells with anti-TGFalpha or anti-EGFR antibody, or with tyrphostin-25 (EGFR inhibitor), significantly impaired the cell migration response to OPN. Other more broad-spectrum tyrosine kinase inhibitors and the growth factor/ receptor interaction inhibitor, suramin, also inhibited OPN-induced migration. Using specific signal transduction pathway inhibitors, we have screened for involvement of MEK (MAP kinase kinase), phosphatidylinositol 3-kinase, phospholipase C (PLC), and protein kinase C (PKC). Results implicated all of these pathways in OPN-induced cell migration, the most pronounced effect being seen with PLC and PKC inhibitors. These results suggest that induction of MEC migration by OPN involves a cascade of events including at least two growth factor/receptor pathways and multiple downstream signal transduction pathways. A number of potential targets are thus provided for strategies aimed at blocking the malignancy-promoting effects of OPN. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/12606946/Osteopontin_induced_migration_of_human_mammary_epithelial_cells_involves_activation_of_EGF_receptor_and_multiple_signal_transduction_pathways_ L2 - http://dx.doi.org/10.1038/sj.onc.1206209 DB - PRIME DP - Unbound Medicine ER -