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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

Long, J.S. and Edwards, J. and Watson, C and Tovey, S and Mair, K.M. and Schiff, R. and Natarajan, V. and Pyne, N.J. and Pyne, S. (2010) 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. Molecular and Cellular Biology, 30 (15). pp. 3827-3841. ISSN 0270-7306

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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 S1P3 is also altered in MCF-7 HER2 cells. In this regard, S1P binding to S1P3 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.