Abstract
Endothelial differentiation gene-encoded G protein-coupled receptors (Edg Rs) Edg-1, Edg-3, and Edg-5 bind sphingosine 1-phosphate (S1P), and Edg-2 and Edg-4 Rs bind lysophosphatidic acid (LPA). LPA and S1P initiate ras- and rho-dependent signaling of cellular growth. Cultured lines of human breast cancer cells (BCCs) express Edg-3 > Edg-4 > Edg-5 > or = Edg-2, without detectable Edg-1, by both assessment of mRNA and Western blots with rabbit and monoclonal mouse anti-Edg R antibodies. BCC proliferation was stimulated significantly by 10(-9) M to 10(-6) M LPA and S1P. Luciferase constructs containing the serum response element (SRE) of growth-related gene promoters reported mean activation of BCCs by LPA and S1P of up to 85-fold. LPA and S1P stimulated BCC secretion of type II insulin-like growth factor (IGF-II) by 2-7-fold, to levels at which exogenous IGF-II stimulated increased proliferation and SRE activation of BCCs. All BCC responses to LPA and S1P were suppressed similarly by pertussis toxin, mitogen-activated protein kinase kinase inhibitors, and C3 exoenzyme inactivation of rho, suggesting mediation by Edg Rs. Monoclonal anti-IGF-II and anti-IGFR1 antibodies suppressed proliferation and SRE reports of BCCs to LPA and S1P by means of up to 65%. Edg Rs thus transduce LPA and S1P enhancement of BCC growth, both directly through SRE and indirectly by enhancing the contribution of IGF-II.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies / pharmacology
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Antibodies, Monoclonal / pharmacology
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Breast Neoplasms
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Cell Division / drug effects*
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DNA-Binding Proteins / analysis
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DNA-Binding Proteins / genetics*
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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I-kappa B Proteins*
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Immediate-Early Proteins / analysis
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Immediate-Early Proteins / genetics*
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Lysophospholipids / pharmacology*
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Mice
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NF-KappaB Inhibitor alpha
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Nuclear Proteins / analysis
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Nuclear Proteins / genetics*
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RNA, Messenger / genetics
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Rabbits
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Receptors, Cell Surface / analysis
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Receptors, Cell Surface / genetics*
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Receptors, G-Protein-Coupled*
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Receptors, Lysophosphatidic Acid
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Receptors, Lysophospholipid
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Reverse Transcriptase Polymerase Chain Reaction
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Sphingosine / analogs & derivatives
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Sphingosine / pharmacokinetics
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Sphingosine / pharmacology
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Transcription Factors / analysis
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Transcription Factors / genetics*
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Transcription, Genetic / drug effects
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Tumor Cells, Cultured
Substances
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Antibodies
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Antibodies, Monoclonal
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DNA-Binding Proteins
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I-kappa B Proteins
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Immediate-Early Proteins
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Lysophospholipids
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NFKBIA protein, human
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Nfkbia protein, mouse
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Nuclear Proteins
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RNA, Messenger
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Receptors, Cell Surface
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Receptors, G-Protein-Coupled
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Receptors, Lysophosphatidic Acid
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Receptors, Lysophospholipid
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Transcription Factors
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NF-KappaB Inhibitor alpha
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sphingosine 1-phosphate
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Sphingosine