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

Mol Cell Biol. 2010 Aug;30(15):3827-41. doi: 10.1128/MCB.01133-09. Epub 2010 Jun 1.


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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Carrier Proteins / pharmacology
  • Cell Line, Tumor
  • Epidermal Growth Factor / genetics
  • Epidermal Growth Factor / metabolism
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Estrogen Receptor alpha
  • Humans
  • Lysophospholipids
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 1 / pharmacology
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinase 3 / pharmacology
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor)
  • Protein Binding / genetics
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • RNA, Small Interfering / pharmacology
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Sphingosine / analogs & derivatives
  • p21-Activated Kinases


  • Carrier Proteins
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Lysophospholipids
  • RNA, Small Interfering
  • Receptors, Estrogen
  • sphingosine 1-phosphate
  • Epidermal Growth Factor
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • ErbB Receptors
  • p21-Activated Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Sphingosine