Oleate Promotes the Proliferation of Breast Cancer Cells via the G Protein-coupled Receptor GPR40

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 Gi/Go, 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. 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 Gi/Go, 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. Epidemiological and animal studies have revealed an association between dietary fatty acids and the incidence of breast cancer (1.Fay M.P. Freedman L.S. Clifford C.K. Midthune D.N. Cancer Res. 1997; 57: 3979-3988PubMed Google Scholar, 2.Lee M.M. Lin S.S. Annu. Rev. Nutr. 2000; 20: 221-248Crossref PubMed Scopus (87) Google Scholar, 3.Rose D.P. Am. J. Clin. Nutr. 1997; 66: 1513-1522Crossref Scopus (192) Google Scholar). In addition, emerging evidence indicates that obesity, which is characterized by hyperlipidemia and elevated circulating free-fatty acids (FFA) 1The abbreviations used are: FFA, free-fatty acid; PI3-K, phosphatidylinositol 3-kinase; GPCR, G protein-coupled receptor; LPA, lysophosphatidic acid; [Ca2+]i, intracellular calcium concentration; BSA, bovine serum albumin; EGF, epidermal growth factor; EGFR, EGF receptor; PKCζ, protein kinase Cζ; ERK1/2, extracellular signal-regulated kinase 1/2; AKT, protein kinase B; PBS, phosphate-buffered saline; siRNA, small interfering RNA; GFP, green fluorescent protein; PLC, phospholipase C; MEK1/2, mitogenic-extracellular signal-regulated kinase 1/2. 1The abbreviations used are: FFA, free-fatty acid; PI3-K, phosphatidylinositol 3-kinase; GPCR, G protein-coupled receptor; LPA, lysophosphatidic acid; [Ca2+]i, intracellular calcium concentration; BSA, bovine serum albumin; EGF, epidermal growth factor; EGFR, EGF receptor; PKCζ, protein kinase Cζ; ERK1/2, extracellular signal-regulated kinase 1/2; AKT, protein kinase B; PBS, phosphate-buffered saline; siRNA, small interfering RNA; GFP, green fluorescent protein; PLC, phospholipase C; MEK1/2, mitogenic-extracellular signal-regulated kinase 1/2. (4.Felber J.P. Golay A. Int. J. Obes. Relat. Metab. Disord. 2002; 26: 39-45Crossref PubMed Scopus (131) Google Scholar), is associated with enhanced cancer risk (5.Calle E.E. Kaaks R. Nat. Rev. Cancer. 2004; 4: 579-591Crossref PubMed Scopus (2631) Google Scholar). However, relative little information exists on the mechanisms by which exogenous FFAs influence breast cancer cell growth. FFAs play pivotal roles in many biological processes. They serve as an abundant source of energy and as precursors of many cellular signaling and structural molecules (6.McArthur M.J. Atshaves B.P. Frolov A. Foxworth W.D. Kier A.B. Schroeder F. J. Lipid Res. 1999; 40: 1371-1383Abstract Full Text Full Text PDF PubMed Google Scholar). As natural ligands for the nuclear receptors peroxisomal proliferated-activated receptors (PPARs), they also control the transcription of several genes involved in lipid and glucose metabolisms (7.Ferre P. Diabetes. 2004; 53: 43-50Crossref PubMed Google Scholar). However, several biological effects appear to be PPAR independent (8.Sauer L.A. Dauchy R.T. Blask D.E. Cancer Res. 2000; 60: 5289-5295PubMed Google Scholar, 9.Louet J.F. Chatelain F. Decaux J.F. Park E.A. Kohl C. Pineau T. Girard J. Pegorier J.P. Biochem. J. 2001; 354: 189-197Crossref PubMed Google Scholar). We have previously reported that the monounsaturated FFA oleate (C18:1) and the saturated FFA palmitate (C16:0), the two most abundant fatty acids in plasma, are not equivalent with respect to their actions on breast cancer cell proliferation and apoptosis (10.Hardy S. Langelier Y. Prentki M. Cancer Res. 2000; 60: 6353-6358PubMed Google Scholar). Oleate stimulates the proliferation of breast cancer cells, whereas palmitate induces apoptosis. Moreover, we found as a general principle that saturated FFAs (palmitic, myristic, and stearic) are proapoptotic, whereas unsaturated FFAs (oleic, linoleic, arachidonic, and eicosapentaenoic) increase proliferation of MDA-MB-231 breast cancer cells (11.Hardy S. El-Assaad W. Przybytkowski E. Joly E. Prentki M. Langelier Y. J. Biol. Chem. 2003; 278: 31861-31870Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar). In addition, a 1:10 molar ratio of oleate versus palmitate was sufficient to annihilate the proapoptotic action of palmitate (10.Hardy S. Langelier Y. Prentki M. Cancer Res. 2000; 60: 6353-6358PubMed Google Scholar). Important differences in the metabolism of these two FFAs in MDA-MB-231 cells contribute to their opposite effects on cell fate. An early enhancement of cardiolipin turnover and a decrease in the level of this mitochondrial phospholipid necessary for cytochrome c retention are involved in the proapoptotic effect of palmitate. By contrast oleate, by channeling palmitate to inert triglyceride stores and by permitting sustained cardiolipin synthesis, not only blocks palmitate-induced apoptosis but also permits cell proliferation (11.Hardy S. El-Assaad W. Przybytkowski E. Joly E. Prentki M. Langelier Y. J. Biol. Chem. 2003; 278: 31861-31870Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar). In addition, oleate but not palmitate appears to act like a growth factor because it stimulates cell proliferation at very low concentrations and rapidly activates phosphatidylinositol 3-kinase (PI3-K) in these cells (10.Hardy S. Langelier Y. Prentki M. Cancer Res. 2000; 60: 6353-6358PubMed Google Scholar). These findings suggest the existence of signaling pathways via membrane receptors such as receptor tyrosine kinases or G protein-coupled receptors (GPCR), which are known to activate PI3-K (12.Grant S. Qiao L. Dent P. Front. Biosci. 2002; 7: 376-389Crossref PubMed Scopus (163) Google Scholar, 13.Yart A. Chap H. Raynal P. Biochim. Biophys. Acta. 2002; 1582: 107-111Crossref PubMed Scopus (58) Google Scholar). Unsaturated FFAs including oleate but not saturated FFAs have been shown to trigger tyrosine phosphorylation and epidermal growth factor receptor (EGFR) activation in an endothelial cell line (14.Vacaresse N. Lajoie-Mazenc I. Auge N. Suc I. Frisach M.F. Salvayre R. Negre-Salvayre A. Circ. Res. 1999; 85: PubMed Scopus Google Scholar). for fatty acid such as S. Rev. Google Scholar), J. C. N. W. P. S. 1999; PubMed Scopus Google Scholar), lysophosphatidic acid Nat. Rev. Cancer. 2003; PubMed Scopus Google Scholar), J. J. Biochem. 2004; PubMed Scopus Google Scholar), and acid T. Y. E. A. N. N. S. T. T. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus (131) Google are of these induces a of cellular including cell proliferation J. J. Biochem. 2004; PubMed Scopus Google Scholar). These effects the activation of a of signaling including the of and protein kinases 2003; PubMed Scopus Google Scholar). independent found that the receptor GPR40 is by and FFAs Y. Y. M. M. R. S. M. Y. H. H. M. R. S. H. H. F. Y. T. S. Y. M. 2003; PubMed Scopus Google Scholar, M. M.M. C. S. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, E. C. Biochem. Biophys. Res. 2003; PubMed Scopus Google Scholar). a on of intracellular calcium concentrations they showed that FFAs in the of bovine serum increased in GPR40 is in Y. Y. M. M. R. S. M. Y. H. H. M. R. S. H. H. F. Y. T. S. Y. M. 2003; PubMed Scopus Google Scholar, M. M.M. C. S. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar), but it is also in E. C. Biochem. Biophys. Res. 2003; PubMed Scopus Google Scholar). GPR40 is in the breast cancer cell line MCF-7 in which but not FFAs to increase T. Y. Biochem. Biophys. Res. 2004; PubMed Scopus (87) Google Scholar). In the we the mechanisms by which oleate the proliferation of the breast cancer cell line MDA-MB-231. The results suggest that pathways are involved in the proliferative action of oleate in these cells and that the oleate effect a In addition, evidence is that the oleate-induced proliferation of breast cancer cells is mediated at least in part GPR40. of fatty acids from was from was from [3H]thymidine was from and from and from LPA, protein kinase from and from breast cancer cell and MCF-7 from the at with in and bovine serum fatty acids by fatty acid at with fatty as E. J. I. Prentki M. Diabetes. 1999; PubMed Scopus Google Scholar). to the was a and the fatty acid was using a fatty acids to the of was to cell growth in and for in (10.Hardy S. Langelier Y. Prentki M. Cancer Res. 2000; 60: 6353-6358PubMed Google Scholar). a in cells or with fatty acids for was with a of [3H]thymidine the of the with a cell from and the on the was by and and as previously J. S. Joly E. Prentki M. Diabetes. 2003; PubMed Scopus Google Scholar). extracellular signal-regulated kinase 1/2 and protein kinase B phosphorylation cells in at and for in a of serum in BSA, cells in phosphate-buffered glucose and for and with oleate or epidermal growth factor for the in was used to levels of and phosphorylation. cells and in protein and by and protein concentrations of the using the of protein by and to was to the using ERK1/2, or in and at in and of at cells and as but and at was at by the at and at and using a concentrations as by M. J. Biol. Chem. Full Text PDF PubMed Scopus Google Scholar). in at for in with of the the GPR40 by or a control using and and to the cells at and for cell growth as RNA that small interfering the control of the by of between and to the The for GPR40 was with the green fluorescent protein and GPR40 gene or a control the by on a cell at and for cell growth as RNA was using RNA was using the was on a using a to the The used as GPR40 and and are as between two with a for was previously showed that the monounsaturated fatty acid oleate stimulates the proliferation of breast cancer cell and that PI3-K is implicated in this effect (10.Hardy S. Langelier Y. Prentki M. Cancer Res. 2000; 60: 6353-6358PubMed Google Scholar). this because the PI3-K A. M.P. Biochem. J. PubMed Scopus Google oleate-induced proliferation of MDA-MB-231 In addition, we showed that PI3-K is rapidly by oleate, signaling a receptor (10.Hardy S. Langelier Y. Prentki M. Cancer Res. 2000; 60: 6353-6358PubMed Google Scholar). the been reported to be by oleate in endothelial cells (14.Vacaresse N. Lajoie-Mazenc I. Auge N. Suc I. Frisach M.F. Salvayre R. Negre-Salvayre A. Circ. Res. 1999; 85: PubMed Scopus Google Scholar), we the activation of the be involved in oleate-induced proliferation of MDA-MB-231 a of A. A. PubMed Scopus Google Scholar), not oleate-induced [3H]thymidine incorporation However, the phosphorylation of induced by EGF In addition, an of the of phosphorylation induced by oleate revealed activation of of However, EGF induced a activation of the at that at and decreased a increase in phosphorylation from of the to receptor H. C. A. A. A. J. 1997; PubMed Scopus Google Scholar). These results that the is not implicated in oleate-induced proliferation of MDA-MB-231 is not by oleate in MDA-MB-231 cells with oleate or palmitate to or EGF for in the or of cells with oleate or to or EGF for the and was from protein to with an and with an The that have been MDA-MB-231 by of Gi/Go, C, Src, MEK1/2, and fatty acid such as are known to act via and to activate PI3-K via G proteins A. Chap H. Raynal P. Biochim. Biophys. Acta. 2002; 1582: 107-111Crossref PubMed Scopus (58) Google Scholar). We the effect of an of proteins J. M. Relat. Biol. Google Scholar), on oleate-induced cell As shown in decreased oleate-induced [3H]thymidine incorporation by The of was with LPA, which been shown to increase cell proliferation activation via proteins S. R. Y. T. Biochem. J. 2000; PubMed Scopus Google Scholar). that the effect of oleate on breast cancer cell proliferation is mediated at least in part by because the action of to is J. M. Relat. Biol. Google Scholar). of caused the activation of a of signaling including of and protein kinases 2003; PubMed Scopus Google Scholar). a role of these signal pathways in the action of oleate on breast cancer cell proliferation, we the effect of of cells with the phospholipase J. Google in an of or proliferation and which are inhibitors of the J.P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and of mitogenic-extracellular signal-regulated kinase 1/2 A. P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), the proliferative effect of oleate by and Moreover, PKCζ, a of PI3-K, appears also to be implicated in the proliferative effect of oleate because a of J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google the oleate-induced proliferation However, this also decreased the proliferation in the control that is for the growth of MDA-MB-231 protein kinase of GPCR, with T. A. M. M. T. T. H. J. Biol. Chem. Full Text PDF PubMed Google not oleate-induced the results are with the that oleate at least in part via and that many signal including PLC, Src, MEK1/2, and PKCζ, may in proliferative Oleate a in and AKT, the of and PI3-K, are of cell proliferation D.P. Biochem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). We the role of and in oleate-induced cell proliferation by using the of and is very high in MDA-MB-231 cells as previously T. A. Cancer Res. 1999; Google Scholar), we to in phosphorylation in to oleate or the control EGF not In oleate and EGF phosphorylation and which increased the of at and The of activation was with of In with data that oleate, but not activates PI3-K (10.Hardy S. Langelier Y. Prentki M. Cancer Res. 2000; 60: 6353-6358PubMed Google Scholar), phosphorylation was not induced by two of that been shown to be in apoptosis not the PI3-K data in the results indicate that the proliferative signal induced by oleate is mediated at least in part via Oleate in the and of was to be by and FFA to by in cells Y. Y. M. M. R. S. M. Y. H. H. M. R. S. H. H. F. Y. T. S. Y. M. 2003; PubMed Scopus Google Scholar, M. M.M. C. S. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, E. C. Biochem. Biophys. Res. 2003; PubMed Scopus Google Scholar). GPR40 is in MDA-MB-231 breast cancer cells at of RNA as we by we of in cells oleate or palmitate In the of BSA, oleate and palmitate caused a rapid increase in by and in the of BSA, a oleate caused a rapid increase in by In palmitate not in the of GPR40 in GPR40 is implicated in the proliferative action of oleate in MDA-MB-231 cells, we to the level of GPR40 in MDA-MB-231 cells using RNA the of is in this cell line not cells with a with a an GPR40 or with a control siRNA, by of cells with a cell the of the GPR40 was by in cells as by a to cell proliferation, cell cells for and for an in with or various concentrations of oleate. The increase in [3H]thymidine incorporation oleate was at concentrations of the FFA in cells the The decreased of GPR40 was in the of caused by low concentrations of the in breast cancer in a We to [3H]thymidine incorporation of GPR40 in the of concentrations of oleate The of by oleate was increased in MDA-MB-231 cells GPR40 at concentrations of and with the control evidence in of a role for GPR40, we to breast cancer cell that GPR40 at the cell GPR40 was at levels to the in MDA-MB-231 cells not this we the effect of GPR40 in the breast cancer cell T47D and not or only in the of oleate (10.Hardy S. Langelier Y. Prentki M. Cancer Res. 2000; 60: 6353-6358PubMed Google Scholar). in these two cell the effect of oleate on [3H]thymidine incorporation was increased by GPR40 was The oleate, in the of GPR40 promotes a proliferative signal in MDA-MB-231 cells but a in T47D and MCF-7 cells that GPR40 at the level is may be that GPR40 is to associated G proteins in MDA-MB-231 cells in the two cell the level of the GPR40 protein may be in T47D and cells the cell the GPR40 at the and results indicate that oleate-induced proliferation of MDA-MB-231 cells is mediated at least in part GPR40. was by the link between the incidence of breast cancer and in animal and studies (1.Fay M.P. Freedman L.S. Clifford C.K. Midthune D.N. Cancer Res. 1997; 57: 3979-3988PubMed Google Scholar, 2.Lee M.M. Lin S.S. Annu. Rev. Nutr. 2000; 20: 221-248Crossref PubMed Scopus (87) Google Scholar, 3.Rose D.P. Am. J. Clin. Nutr. 1997; 66: 1513-1522Crossref Scopus (192) Google Scholar). The for this is this we a of studies on the abundant fatty oleate, because it been shown to the proliferation of breast cancer cells (10.Hardy S. Langelier Y. Prentki M. Cancer Res. 2000; 60: 6353-6358PubMed Google Scholar). of signaling at the level of Src, MEK1/2, PI3-K, or in a of oleate-induced synthesis, that or of from pathways is necessary to cells to in to oleate. We also found that a is implicated in the proliferative signal induced by this monounsaturated a very of G proteins J. M. Relat. Biol. Google Scholar), and oleate-induced proliferation, the of proteins in this process. previously been shown to the proliferation of via to S. R. Y. T. Biochem. J. 2000; PubMed Scopus Google Scholar). In addition, the that we provide evidence that the GPR40 is implicated in the proliferative action of oleate is in evidence for a role of a in oleate is for a role in action been to the GPR40 Y. Y. M. M. R. S. M. Y. H. H. M. R. S. H. H. F. Y. T. S. Y. M. 2003; PubMed Scopus Google Scholar). of evidence that GPR40 is implicated in oleate-induced proliferation of breast cancer is increased in to oleate in MDA-MB-231 of GPR40 amplified the oleate-induced cell proliferation in breast cancer cell that oleate via this FFA receptor in these of MDA-MB-231 cells with an GPR40 the proliferative effect of oleate. of signaling to cell growth previously been for including and J. J. Biochem. 2004; PubMed Scopus Google Scholar). only a of the proliferative effect of oleate with GPR40 was we on that receptors for oleate or signaling pathways in oleate-induced cell with several to biological actions M. M. S. R. Y. R. A. R. J. Biochim. Biophys. Acta. 2002; 1582: PubMed Scopus Google Scholar), and it may also act via a to cell growth J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). GPCR, was A. T. S. T. M. Y. S. Nat. PubMed Scopus Google Scholar), and to oleate-induced proliferation of breast cancer cells to be the the of GPR40 in oleate-induced proliferation is to be because the not Moreover, as we not have information on GPR40 protein level and in these cells, it is to The decrease in oleate-induced proliferation with the suggests a role of this phospholipase in this process. is a of signaling A.B. 1997; PubMed Scopus Google Scholar). that oleate to the receptor activates of phosphatidylinositol and activates and calcium from the M. M.J. PubMed Scopus Google Scholar). and calcium are that have been reported to for breast cancer cell proliferation S. A. P. C. A. C. S. J. 2003; PubMed Scopus Google Scholar). Moreover, several studies have shown that unsaturated including oleate, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, results that oleate and palmitate caused a rapid and transient increase in in MDA-MB-231 cells in the of However, in the of BSA, palmitate not increase in contrast to oleate, which a robust Ca2+ results have been in MCF-7 breast cancer cells T. Y. Biochem. Biophys. Res. 2004; PubMed Scopus (87) Google Scholar). The between these two fatty acids be in part by a of oleate for GPR40. In to oleate a for A. PubMed Scopus Google and cellular A. PubMed Scopus Google Scholar). oleate may breast cancer cell proliferation by to GPR40 palmitate. In addition, as shown in studies (10.Hardy S. Langelier Y. Prentki M. Cancer Res. 2000; 60: 6353-6358PubMed Google Scholar, S. El-Assaad W. Przybytkowski E. Joly E. Prentki M. Langelier Y. J. Biol. Chem. 2003; 278: 31861-31870Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar), differences in the metabolism of these two fatty acids are involved in their opposite effects on cell the saturated fatty acid palmitate induces apoptosis of breast cancer cells via a that enhanced cardiolipin turnover and a of this mitochondrial whereas the unsaturated fatty acid oleate, by cardiolipin synthesis, permits cell The rapid and transient increase in induced by oleate suggests calcium from intracellular stores that protein activation in to many receptor J. J. Biochem. 2004; PubMed Scopus Google Scholar). these results the that oleate in MDA-MB-231 cell proliferation via GPR40 to a protein and via the GPR40 is to in cells and cells GPR40 Y. Y. M. M. R. S. M. Y. H. H. M. R. S. H. H. F. Y. T. S. Y. M. 2003; PubMed Scopus Google Scholar, M. M.M. C. S. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). However, GPR40 is also to and in MCF-7 cells T. Y. Biochem. Biophys. Res. 2004; PubMed Scopus (87) Google Scholar). in to oleate-induced proliferation of MDA-MB-231 cells via GPR40 is to Gi/Go, because but not the proliferative effect of oleate in these An to proteins been shown to be by the unsaturated FFA and to a decrease in levels T. Y. E. A. N. N. S. T. T. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus (131) Google Scholar). The of several proteins are to in a decrease in levels R. PubMed Scopus Google Scholar). However, levels not by oleate in MDA-MB-231 cells with LPA, which a in the cellular not is with the that a protein kinase not oleate-induced is that many of the biological effects from the activation of proteins are not mediated via the J. S. W. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of the protein J. S. W. 2000; Full Text Full Text PDF PubMed Scopus Google and Ca2+ M. T. T. Y. A. M. S. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The increase in induced by oleate appears to be mediated in part by the and as by the using The of and ERK1/2, the of MEK1/2, is for cell and proliferation mediated by growth A. M. A. M. W. M. F. J. PubMed Scopus Google Scholar, H. 2001; Google Scholar). with this a reported that oleate induces activation via GPR40 in the line Y. Y. M. M. R. S. M. Y. H. H. M. R. S. H. H. F. Y. T. S. Y. M. 2003; PubMed Scopus Google Scholar). is rapidly by oleate in MDA-MB-231 cells, but not by palmitate. cell and is known to in cell proliferation and D.P. Biochem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). of may to the of the via and the activation of a of signaling including and J. S. Joly E. Prentki M. Diabetes. 2003; PubMed Scopus Google Scholar, H. C. A. A. A. J. 1997; PubMed Scopus Google Scholar). However, oleate not activation in the cellular we and with not oleate-induced Oleate activate the in endothelial cells (14.Vacaresse N. Lajoie-Mazenc I. Auge N. Suc I. Frisach M.F. Salvayre R. Negre-Salvayre A. Circ. Res. 1999; 85: PubMed Scopus Google but effect on tyrosine phosphorylation in breast cancer cells A. Biol. 1997; PubMed Scopus Google Scholar). of GPR40 by oleate to the of growth factor receptors to tyrosine kinases and the activation of is a to GPR40 activate PI3-K as in R.T. Nat. Rev. Biol. 2002; PubMed Scopus Google Scholar). In the and results in this suggest the of in to oleate in The unsaturated FFA to GPR40 and FFA to and in the activation of PI3-K, AKT, and Ca2+ cell growth. be that receptors are also implicated in oleate-induced activation of the PLC, Src, MEK1/2, and pathways that may in the proliferative these data provide a for the action of oleate in breast cancer cells in to cell growth by that this monounsaturated FFA as an extracellular signaling to breast cancer cell proliferation via the FFA receptor GPR40. GPR40 is not only a receptor that may in the control of by FFA, but it also play an role in the control of cell by the be that GPR40 a link between fat and cancer. In this the emerging evidence suggest an association between obesity, and several in and breast cancer (5.Calle E.E. Kaaks R. Nat. Rev. Cancer. 2004; 4: 579-591Crossref PubMed Scopus (2631) Google Scholar). it be that of GPR40 in a of to in a in unsaturated fatty We for the of the

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