Sphingosine kinase 1 induces tolerance to human epidermal growth factor receptor 2 and prevents formation of a migratory phenotype in response to sphingosine 1-phosphate in estrogen receptor-positive breast cancer cells.
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.
Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.
Jaclyn S
JS
Long
Joanne
J
Edwards
Carol
C
Watson
Sian
S
Tovey
Kirsty M
KM
Mair
Rachel
R
Schiff
Viswanathan
V
Natarajan
Nigel J
NJ
Pyne
Susan
S
Pyne
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D047628:Estrogen Receptor alpha; D006801:Humans; D008246:Lysophospholipids; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor); D011485:Protein Binding / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives; D054462:p21-Activated Kinases; D000099157:Sphingosine Kinase
D002352:Carrier Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D047628:Estrogen Receptor alpha; D008246:Lysophospholipids; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017853:Phosphotransferases (Alcohol Group Acceptor); D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D013110:Sphingosine; D054462:p21-Activated Kinases; D000099157:Sphingosine Kinase; C506487:ESR1 protein, human; C060506:sphingosine 1-phosphate