Abstract
We demonstrate here a new concept termed "oncogene tolerance" whereby human EGF receptor 2 (HER2) increases sphingosine kinase 1 (SK1) expression in estrogen receptor-positive (ER(+)) MCF-7 HER2 cells and SK1, in turn, limits HER2 expression in a negative-feedback manner. The HER2-dependent increase in SK1 expression also limits p21-activated protein kinase 1 (p65 PAK1) and extracellular signal regulated kinase 1/2 (ERK-1/2) signaling. Sphingosine 1-phosphate signaling via S1P(3) is also altered in MCF-7 HER2 cells. In this regard, S1P binding to S1P(3) induces a migratory phenotype via an SK1-dependent mechanism in ER(+) MCF-7 Neo cells, which lack HER2. This involves the S1P stimulated accumulation of phosphorylated ERK-1/2 and actin into membrane ruffles/lamellipodia and migration. In contrast, S1P failed to promote redistribution of phosphorylated ERK-1/2 and actin into membrane ruffles/lamellipodia or migration of MCF-7 HER2 cells. However, a migratory phenotype in these cells could be induced in response to S1P when SK1 expression had been knocked down with a specific siRNA or when recombinant PAK1 was ectopically overexpressed. Thus, the HER2-dependent increase in SK1 expression functions to desensitize the S1P-induced formation of a migratory phenotype. This is correlated with improved prognosis in patients who have a low HER1-3/SK1 expression ratio in their ER(+) breast cancer tumors compared to patients that have a high HER1-3/SK1 expression ratio.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Carrier Proteins / pharmacology
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Cell Line, Tumor
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Epidermal Growth Factor / genetics
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Epidermal Growth Factor / metabolism
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Estrogen Receptor alpha
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Humans
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Lysophospholipids
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 1 / pharmacology
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mitogen-Activated Protein Kinase 3 / pharmacology
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Phosphorylation
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Phosphotransferases (Alcohol Group Acceptor)
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Protein Binding / genetics
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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RNA, Small Interfering / pharmacology
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Receptors, Estrogen / genetics
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Receptors, Estrogen / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Sphingosine / analogs & derivatives
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p21-Activated Kinases
Substances
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Carrier Proteins
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ESR1 protein, human
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Estrogen Receptor alpha
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Lysophospholipids
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RNA, Small Interfering
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Receptors, Estrogen
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sphingosine 1-phosphate
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Epidermal Growth Factor
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase
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ErbB Receptors
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p21-Activated Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Sphingosine