GD3 synthase expression enhances proliferation and tumor growth of MDA-MB-231 breast cancer cells through c-Met activation.
Abstract
The disialoganglioside GD3 is over-expressed in about 50 % of invasive ductal breast carcinoma and the GD3 synthase gene (ST8SIA1) displayed higher expression among estrogen receptor negative breast cancer tumors, associated with a decreased overall survival of breast cancer patients. However, no relationship between ganglioside expression and breast cancer development and aggressiveness has been reported. We have previously shown that the over-expression of GD3 synthase induces the accumulation of b- and c-series gangliosides (GD3, GD2 and GT3) at the cell surface of MDA-MB-231 breast cancer cells together with the acquisition of a proliferative phenotype in absence of serum. Here we show that PI3K/Akt and MEK/ERK pathways are constitutively activated in GD3 synthase expressing cells. Analysis of tyrosine kinase receptors phosphorylation shows a specific c-Met constitutive activation in GD3 synthase expressing cells, in absence of its ligand the HGF/SF. In addition, inhibition of c-Met or downstream signaling pathways reverses the proliferative phenotype. We also show that GD3 synthase expression enhances tumor growth in severe combined immunodeficiency (SCID) mice. Finally, a higher expression of ST8SIA1 and MET in the basal subtype of human breast tumors are observed. Altogether, our results demonstrate that GD3 synthase expression is sufficient to enhance the tumorigenicity of MDA-MB-231 breast cancer cells through a ganglioside-dependent activation of c-Met receptor.