Mol Cell Biol 2010,
PMID: 20516217
Long, Jaclyn S; Edwards, Joanne; Watson, Carol; Tovey, Sian; Mair, Kirsty M; Schiff, Rachel; Natarajan, Viswanathan; Pyne, Nigel J; Pyne, Susan
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.
Diseases/Pathways annotated by Medline MESH: Breast Neoplasms
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Text Mining Data
sphingosine kinase 1 (SK1) → EGF: "
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
"
extracellular signal regulated kinase 1/2 → p21: "
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
"
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