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., Edwards, J. , Watson, C., Tovey, S., Mair, K. M., Schiff, R., Natarajan, V., 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. (doi: 10.1128/MCB.01133-09)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Edwards, Professor Joanne
• Authors: Long, J. S., Edwards, J., Watson, C., Tovey, S., Mair, K. M., Schiff, R., Natarajan, V., Pyne, N. J., and Pyne, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular and Cellular Biology
• ISSN: 0270-7306