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J. Biol. Chem., Vol. 280, Issue 14, 13285-13291, April 8, 2005

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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**

From the Molecular Nutrition Unit, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, the Institut du Cancer de Montréal, and the Departments of ^¶Medicine and ^**Nutrition and the Montréal Diabetes Research Center, Université de Montréal, Montréal, Québec H2L 4M1, Canada

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 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 G_i/G_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 phosphorylation. Overexpressing in these cells the G protein-coupled receptor 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 phosphatidylinositol 3-kinase/protein kinase B signaling pathways are implicated in the proliferative signal induced by oleate and that these effects are mediated at least in part via the G protein-coupled receptor 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.

Received for publication, September 22, 2004 , and in revised form, January 10, 2005.

^* This work was supported by a studentship from the Fonds Québécois de la Recherche sur la Nature et les Technologies (to S. H.) and by research grants from the Canadian Cancer Etiology Research Network, the Montreal Breast Cancer Foundation, and the Fondation René Malo/Institut du Cancer de Montréal (to Y. L., E. J., and M. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Hôpital Notre-Dame, Y-5603, 1560 Sherbrooke Est., Montréal, Québec H2L 4M1, Canada. Tel.: 514-890-8000 (ext. 26827); Fax: 514-412-7590; E-mail: yves.langelier{at}umontreal.ca.

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