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A more recent version of this article appeared on April 8, 2005
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Papers In Press, published online ahead of print February 4, 2005
J. Biol. Chem, 10.1074/jbc.M410922200
Submitted on September 22, 2004
Revised on February 4, 2005
Accepted on February 4, 2005

Oleate promotes the proliferation of breast cancer cells via the G protein-coupled receptor GPR40

Serge Hardy, Geneviève G. St-Onge, Érik Joly, Yves Langelier, and Marc Prentki

Centre de recherche du CHUM, Université de Montréal, Montréal, Québec H2L 4M1

Corresponding Author: yves.langelier{at}umontreal.ca

Evidence from epidemiological studies and animal models suggests a link between high levels of dietary fat intake and risk of breast cancer. In addition, obesity, in which circulating lipids are elevated, is associated with increased risk of various cancers. Relative to this point, we previously showed that oleate stimulates the proliferation of breast cancer cells and that phosphatidylinositol 3-kinase (PI3-K) plays a role in this process. Nonetheless, questions remain regarding the precise mechanism(s) by which oleate promotes breast cancer cell growth. Pharmacological inhibitors of the GTP binding proteins Gi/o, phospholipase C, src and mitogenic-extracellular signal-regulated kinase 1/2 (MEK 1/2) decreased oleate-induced [3H]-thymidine incorporation in the breast cancer cell line MDA-MB-231. In addition, oleate caused a rapid and transient rise in cytosolic Ca2+ and an increase in protein kinase B (AKT) phosphorylation. Overexpressing in these cells the G-protein-coupled receptor (GPCR) GPR40, a fatty acid receptor, amplified oleate-induced proliferation, whereas silencing the GPR40 gene using RNA interference decreased it. Overexpressing GPR40 in T47D and MCF-7 breast cancer cells that are poorly responsive to oleate allowed a robust proliferative action of oleate. The data indicate that the phospholipase C, MEK 1/2, src and PI3-K/AKT signaling pathways are implicated in the proliferative signal induced by oleate and that these effects are mediated at least in part via the GPCR GPR40. The results suggest that GPR40 is implicated in the control of breast cancer cell growth by fatty acids and that GPR40 may provide a link between fat and cancer.


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