For several years, lipids and especially n-3 and n-6
polyunsaturated fatty acids (PUFAs) receive much attention in human health. Epidemiological studies tend to correlate a PUFA-rich diet with a reduced incidence of cancer, including breast cancer. However, the molecular and cellular mechanisms supporting the effect of PUFAs in breast cancer cells remain relatively unknown. Here, we review some recent progress in understanding the impact that PUFA may have on breast cancer cell proliferation, apoptosis, migration, and invasion. While most of the results obtained with docosahexaenoic acid and/or eicosapentaenoic acid show a decrease of tumor cell proliferation and/or aggressivity, there is some evidence that other lipids, which accumulate in breast cancer tissues, such as arachidonic acid may have opposite effects. Finally, lipids and especially PUFAs appear as potential adjuvants to conventional cancer therapy.
1. Introduction
Breast cancer is one of the cancers most frequently observed in industrialized countries, and the one with the highest incidence in women. Epidemiological studies have shown that the rate of breast cancer is 4 to 5 times higher in Western countries that in Japan [1, 2] suggesting that diet, and particularly diet rich in n-3 and n-6 long-chain polyunsaturated fatty acids (PUFAs), may have an influence on tumor emergence [3–6]. Also high dietary intake of fish is associated with a lower incidence of cancers including breast cancer [7–9].
However cohort studies that examined the effect of n-3 PUFAs on breast cancer incidence yielded mixed results, and most of them did not show a significant association between n-3 PUFAs consumption and breast cancer risk [10, 11]. Nevertheless the Women’s Intervention Nutrition Study (WINS) provided evidence that a reduction in dietary fat intake to 22% of total energy intake led to a 24% reduction in the recurrence rate of breast cancer [12]. Then, is fat beneficial or not? Probably not in excess, and mainly PUFAs rich fat rather than saturated fat.
Several authors have shown that n-3 PUFAs, namely, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have demonstrable anticancer properties both in vitro and in vivo. However, the mechanisms behind the benefits are not clear [13–16]. This paper aims to give a rapid overview of the effect of PUFAs on breast cancer cell proliferation, apoptosis, migration, and invasion.
2. Effect of n-3 PUFAs on Breast Cancer Cell Proliferation and Apoptosis
Several studies showed that DHA and EPA together or alone inhibit the growth of breast cancer cell lines [17–19]. Some additional evidence hints that DHA not only acts as an antiproliferative agent by lengthening the cell cycle between the G2/M transition [20], but is also a proapoptotic factor, increasing Bcl-2, procaspase-8, and caspase-3 activity in breast cancer cell lines [21–23]. In addition, DHA has been shown to affect cell proliferation whatever it comes from fish oil or microalgae [24].
Activation of the p44/42 mitogen-activated protein kinase (MAPK) pathway plays a major role in regulating cell growth and survival in breast cancer cells [25] and is protective against apoptosis through phosphorylation of Bad [26]. DHA-induced apoptosis of breast cancer cells was also associated with up-regulation of the transmembrane heparan sulfate proteoglycan syndecan-1 [27]. Moreover increase of syndecan-1 impairs signaling of the MAPK pathway by inhibiting phosphorylation of MEK, Erk, and Bad, that results in apoptosis induction in breast cancer cells [28].
Incorporation of n-3 PUFAs in membranes decreased arachidonic acid (AA) content and n-6/n-3 PUFA ratio in the membranes, without modifying the unsaturation index [29]. Consequently, the modification of AA metabolism, especially the inhibition of the production of eicosanoids, may explain in part the antiproliferative and proapoptotic effect of n-3 PUFAs [16, 30]. Whereas low doses of DHA and EPA did not change cell susceptibility to oxidative stress [29], several works report increased lipid peroxidation and ROS production in n-3 PUFA-treated cancer cells associated with growth arrest and apoptosis [31–38]. Some differences between DHA and EPA may be noted as reported in glioblastoma cells where the levels of reactive oxygen species and thiobarbituric acid-reactive substances were significantly higher in DHA-treated cells than in EPA- and AA-treated groups [33]. Glutathione is a key molecule in cellular redox homeostasis, and its reduced form (GSH) content was decreased in DHA-supplemented cells [33, 35]. The activity of cytosolic glutathione peroxidase was decreased in breast cancer cells treated with DHA [37] whereas main antioxidant enzyme activities (i.e., superoxide dismutase and catalase) were increased [33, 37]. The use of various antioxidant molecules was shown to inhibit n-3 PUFA-induced apoptosis suggesting the involvement of lipid peroxidation-derived ROS [31–38].
Then PUFAs appeared as proliferation inhibitors and apoptosis inducers in breast cancer cell lines and animal models, at least in part through MAPK and ROS pathways [28, 39].
3. Effect of n-3 PUFAs on Lipid Rafts and Signaling in Breast Cancer Cells
The n-3 PUFAs may exert their growth inhibitory effects on cancer cells by altering the plasma membrane composition and associated signaling events [40]. One emerging view is that DHA-containing phospholipids modify the biophysical organization of the plasma membrane which in turn modifies protein activity and cellular function [41–45]. Model membrane studies suggest that the energetically less favorable interaction between cholesterol and PUFA, especially DHA, promotes lateral phase segregation into sterol-poor/PUFA-rich and sterol-rich/saturated fatty acid-rich microdomains [44, 46, 47]. Since lipid rafts are predominantly enriched in saturated fatty acids-containing sphingolipid and cholesterol, the incorporation of PUFA, especially DHA, determines in breast cancer cells a disruption of lipid rafts and a formation of the PUFA-rich/cholesterol-poor nonraft domains [43].
The effect of n-3 PUFAs on lipid rafts and their signaling pathways has been studied in several cell types with cancerous origin or not [48]. Particularly, the raft marker caveolin-1 is partially displaced on treatment with DHA and EPA [49, 50]. In the MDA-MB-231 breast cancer cell line, Altenburg and Siddiqui, 2009 showed that n-3 PUFAs exposure resulted in a decreased level of the chemokine receptor CXCR4, which requires intact lipid rafts for signaling [51]. Schley et al, 2007 have shown in the MDA-MB-231 cell line that a combination of EPA and DHA induces a modification in the lipid raft composition including fatty acids, phospholipids, cholesterol, ceramides, and DAG content of membrane rafts [52]. These alterations of lipid content are accompanied by a decrease of EGFR in rafts and an increased whole cells level of phosphorylated EGFR and p38 MAPK [52]. Increased phosphorylation of EGFR and p38 was already reported as a proapoptotic signal in cancer cells [53–55], and especially in the MDA-MB-231 breast cancer cell line [52, 56]. Furthermore DHA induces the upregulation of EGFR tyrosine phosphorylation and the increase of EGFR association with the Sos1 guanine nucleotide protein exchange factor in cancer cell lines including MDA-MB-231 [57]. These data suggest that EGF/Ras/Erk signaling is being disrupted in DHA-treated breast cancer cells by the exclusion of EGFR protein from lipid raft microdomains [52, 57].
Corsetto et al. have recently examined the PUFA incorporation in breast cancer lipid rafts and showed that PUFA are incorporated preferentially in phosphatidylinositol, phosphatidylserine, and phosphatidylcholine that may be relevant to the formation of biologically active metabolites such as prostaglandins, prostacyclins, leukotrienes, resolvines, and protectines [43]. These authors conclude that while EPA may contribute to cell apoptosis mainly through a decrease of AA concentration in lipid raft phospholipids, DHA may change the biophysical properties of lipid rafts decreasing the content of cholesterol and the distribution of key proteins such as EGFR, Src, heterotrimeric G-proteins subunits, or sphyngomyelinase. Indeed DHA decreases the sphingomyelin content in lipid rafts of breast cancer cell lines [43]. This might be due to an activation of sphingomyelinase, leading to the production of ceramide which is well known to be associated with apoptosis and cellular stress [58–61]. Increased activity of the neutral sphingomyelinase in response to EPA and DHA treatment was previously reported in Jurkat leukemic cells [16].
Recently n-3 PUFA-mediated alteration of lipid rafts was linked to oxidative stress modulation. The treatment of rat hepatocytes with EPA increases ethanol-induced oxidative stress via lipid raft aggregation and subsequent phospholipase Cγ translocation into these microdomains [41]. EPA incorporates preferentially into nonraft membrane region, leading to raft cholesterol increase [41]. In a different model, that is, human endothelial cells, DHA reduced oxidative-stress-induced calcium influx through modification of lipid raft composition [45]. Then what is the effect of n-3 PUFA-mediated remodeling of lipid rafts in breast cancer cells with respect to oxidative stress?
4. PUFA-Induced Inhibition of Cell Migration and Invasiveness
Because metastasis is the leading cause of death from breast cancer, reducing the invasive potential of breast cancer cells is almost as important as destroying in the primary tumor. Recently, we showed that DHA reduces the invasive potential of the MDA-MB-231 breast cancer cell line [21]. Interestingly cholesterol levels in lipid rafts, which are altered by n-3 PUFA [52], are critical for the migration, invasion, and angiogenesis of breast cancer cells [62]. In this study, methyl-β-cyclodextrin reduced uPAR and matrix metalloproteinase-9 (MMP-9) colocalization in lipid rafts and inhibited breast carcinoma cell migration and invasion. The decreased expression of uPAR and MMP-9 was reversed by cholesterol supplementation [62]. In addition the DHA-induced reduction of breast cancer cells migration may also be due to inhibition of voltage-gated Na+ channels [63, 64]. Indeed DHA inhibits voltage-gated Na+ channels (neonatal Nav1.5) in a dose-dependent manner, and tetrodoxin, a compound that specifically blocks this type of channels, reduces MDA-MB-231 cell migration at the same level that observed in the presence of DHA [64]. The authors concluded that DHA-induced suppression of cellular migration occurred primarily via down-regulation of voltage-gated Na+ channel mRNA and functional protein expression [64]. Moreover voltage-gated Na+ channels localization in lipid rafts, such as shown in cardiac cells [65], may be affected by PUFAs [63].
One of the hallmarks for breast cancer metastasis is the over expression of chemokine receptors, which leads to migration of the cancerous cells to surrounding tissues [66–68]. The transmembrane G protein-coupled receptor CXCR4 is the most prominent chemokine receptor expressed in breast cancer cells (but not in normal breast cells) and represent a major factor in breast cancer metastasis due to migration of the cancerous cells through signaling by its unique ligand (i.e., CXCL12) to surrounding tissues [67, 69–71]. Exposure of MDA-MB-231 breast cancer cells to n-3 PUFAs results in decreased surface levels of CXCR4 in a time- and dose-dependent manner [51]. Migration of cells toward the CXCR4 ligand CXCL12 was also significantly reduced on n-3 PUFA treatment [51]. These data suggest that the disruption of required lipid raft domains for CXCR4 signaling and the displacement of CXCR4 from the lipid raft domains are potential mechanisms behind the inhibited migratory response after DHA and EPA treatment [51].
5. n-6 PUFAs as Promoters of Breast Cancer Cell Proliferation and Invasiveness
Some recent studies focused on the negative effect lipids may have on breast cancer evolution and/or emergence. Both LDL and unsaturated fatty acids have been demonstrated to increase proliferation of estrogen receptor alpha negative (ER-) breast cancer cells [72–74] suggesting that higher levels of circulating lipoproteins and free fatty acids, which are common in obesity, metabolic syndrome, and high-fat diets, may themselves promote aggressive characteristics of breast cancer. The observations by Antalis et al. that triple negative breast cancer cell lines (i.e., lacking ER, progesterone receptor, and ERBB2), namely, MDA-MB-231 and MDA-MB-436, had many more lipids droplets as compared to the ER+ MCF-7 cell line leads to the investigation of neutral lipid composition and metabolism in these cells [75]. Elevated levels of triacylglycerol and cholesteryl esters were found, with a greater proportion of cholesteryl ester relative to triacylglycerol [75]. Moreover the acylCoA : cholesterol acyltransferase 1 (ACAT1) expression was upregulated as well as the LDL uptake in triple negative cells compared to ER+ cells [75]. These data are in agreement with transcriptomic results showing that ACAT1 is more highly expressed in human breast cancer cell lines [76] and human breast tumors [77–80] that were characterized as basal, triple negative, or ER−. Interestingly, LDL was shown to stimulate proliferation of ER-cells in a manner dependent from ACAT1 activity [75, 81]. High ACAT1 activity was associated with a higher expression of LDL receptor and both depletion in LDL and ACAT1 inhibition decreased cell migration [81]. This supports the association of lipid accumulation with aggressive behavior in ER-breast cancer cell lines.
Examining fatty acid composition of breast cancer tissues Chang et al. observed higher levels of AA, stearic acid, and DHA in tumoral tissue by comparison with healthy tissue of the same patient [82]. They also observed an increased expression of PPARα in breast cancer tissues [82]. Furthermore, the AA contents of the breast cancer tissues were positively correlated with mammary carcinogenesis [82–84]. Besides these in vivo data, AA was found to stimulate the growth rate of three breast cancer cell lines (one triple negative and two triple positive) in correlation with PPARα expression and activity [82]. Invasiveness of breast cancer cells is increased by AA and was recently shown to be dependent of TGF-β-activated kinase-1 [85] and ubiquitination of collagen-IV [86]. Treatment of MDA-MB-231 cells with AA also stimulates a signaling pathway dependent of phospholipase-A2-α, Src, Erk1/2, and lipoxygenase activities [87]. The mammalian target of rapamycin (mTOR) signaling pathway, which is upregulated in many cancers, was stimulated in breast cancer cultured cells treated with AA [88]. This mTOR pathway seems to be involved in AA-induced proliferation and angiogenesis of breast tumor [88]. In addition, esterification of AA by acyl-CoA synthetase-4 (ACSL4) may play a causal role in the aggressive phenotype of breast cancer cells through the compartmentalization of AA release in mitochondria, a mechanism that serves to drive the specific lipoxygenase metabolism of AA [89].
Like AA, linoleic acid promotes the proliferation and the migration of cancer cells. Linoleic acid induces expression of plasminogen activator inhibitor-1, proliferation, migration, and invasion of breast cancer cells [90, 91]. Linoleic acid also induces focal adhesion kinase, NF-κB activation, matrix metalloproteinase-2 and -9 secretion, and finally cell migration and invasion [92]. By contrast, conjugated linoleic acid (CLA), converted from plant linoleic acid by rumen bacteria, displays the opposite anticancer effect [93]. CLA has been shown to promote breast cancer cell apoptosis through diverse signaling pathways such as estrogen receptor, MAPK, and PI3K/Akt signaling pathways [94–97]. Breast cancer cell invasion is reduced after treatment with CLA, and this may involve PPARγ and E-cadherin/β-catenin pathway and/or estrogen receptor and protein phosphatase-2A depending of the cell type [98, 99]. Caveolin-1 expression is also decreased in breast cancer cells treated with CLA [100], leading to lipid raft alteration as observed with n-3 PUFAs.
6. Breast Cancer Risk Associated with n-6 and n-3 PUFAs in Human
Animal models have demonstrated that long chain PUFAs have differential effects on mammary tumorigenesis based on double bond position and meta-analyses of mouse mammary tumor models have suggested that n-6 PUFAs, such as linoleic acid and AA have a tumor promoting effect [101–103]. A potential mechanism behind the cancer promoting effects of n-6 PUFAs is through the production of proinflammatory eicosanoids such as prostaglandin E2, which promotes angiogenesis and hinders apoptosis. Alternatively, n-3 PUFAs, such as EPA and DHA are the precursor molecules to eicosanoids that are less inflammatory when compared to AA-derived prostanoids [42, 104]. In a case-control study with US women, Bagga et al. showed that total n-6 PUFAs may be contributing to the high risk of breast cancer in the US, and that n-3 PUFAs may have a protective effect [105]. A recent cohort study in China also shows a statistically significant interaction between n-6 PUFA intake, n-3 PUFA intake, and breast cancer risk. Women with lower intake of n-3 PUFA and higher intake of n-6 PUFA had an increased risk for breast cancer compared to women with higher intake of n-3 PUFAs and lower intake of n-6 PUFAs [106]. Accordingly a previous study points out an increased breast cancer risk in Singapore Chinese women belonging to the highest quartile of n-6 fatty acid consumption among subjects who consumed low levels of marine n-3 fatty acids [107]. To conclude, the relative amounts of n-6 PUFA to n-3 PUFAs may be more important for breast cancer risk than individual dietary amounts of these fatty acids.
7. Conclusion
High fat diets, obesity, and metabolic syndrome leading to high circulating level of lipoproteins are harmful for more than one aspect, but they may also be aggravating for breast cancer by stimulating tumor proliferation and metastasis. On the contrary PUFAs are generally regarded as safe compounds that are well tolerated and produce few side effects. Their effects on nontumorigenic cells have not been fully elucidated, but some studies suggest that when provided at concentrations that inhibit tumor cell growth, n-3 PUFA exert little or no cytotoxic effects on normal breast cells [17, 18, 108]. Clinical studies are ongoing to show the DHA-improved outcome of chemotherapy in patients with metastatic breast cancer [109, 110]. DHA may also have interesting synergistic effects with other compounds such as with curcumin [111]. Then n-3 PUFA may now be considered as powerful nontoxic adjuvant of canonical anticancer treatments [112], especially for patient suffering from late stage metastatic breast cancer. However, further investigation will be required to determine whether the effects observed in the breast cancer cell lines or animal models will be replicated with primary breast cancer cells, and moreover to see if the in vitro observed effects will be translated in vivo. Also, it will be important to determine the ratio of n-3 versus n-6 PUFAs needed to be consumed for the beneficiary effect to be achieved.
HolmesM. D.WillettW. C.Does diet affect breast cancer risk?2004641701782-s2.0-434457843210.1186/bcr909KinlenL. J.Diet and breast cancer19914724624692-s2.0-0025732922BlanckaertV. D.SchellingM. E.ElstadC. A.MeadowsG. G.Differential growth factor production, secretion, and response by high and low metastatic variants of B16BL6 melanoma19935317407540812-s2.0-0027165486GreenwaldP.Clinical trials of breast and prostate cancer prevention20011311176S178S2-s2.0-0035181984MolokhiaE. A.PerkinsA.Preventing Cancer20083546096232-s2.0-5334912020710.1016/j.pop.2008.07.009BerquinI. M.EdwardsI. J.ChenY. Q.Multi-targeted therapy of cancer by omega-3 fatty acids200826923633772-s2.0-5134913787610.1016/j.canlet.2008.03.044HurstingS. D.ThornquistM.HendersonM. M.Types of dietary fat and the incidence of cancer at five sites19901932422532-s2.0-002530216310.1016/0091-7435(90)90025-FKaizerL.BoydN. F.KriukovV.TritchlerD.Fish consumption and breast cancer risk: an ecological study198912161682-s2.0-0024535082SasakiS.HoracsekM.KestelootH.An ecological study of the relationship between dietary fat intake and breast cancer mortality19932221872022-s2.0-002723181910.1006/pmed.1993.1016HolmesM. D.LiuS.HankinsonS. E.ColditzG. A.HunterD. J.WillettW. C.Dietary carbohydrates, fiber, and breast cancer risk200415987327392-s2.0-234252780910.1093/aje/kwh112MacLeanC. H.NewberryS. J.MojicaW. A.KhannaP.IssaA. M.SuttorpM. J.LimY. W.TrainaS. B.HiltonL.GarlandR.MortonS. C.Effects of omega-3 fatty acids on cancer risk: a systematic review200629544034152-s2.0-3134447829410.1001/jama.295.4.403ChlebowskiR. T.BlackburnG. L.ThomsonC. A.NixonD. W.ShapiroA.HoyM. K.GoodmanM. T.GiulianoA. E.KaranjaN.McAndrewP.HudisC.ButlerJ.MerkelD.KristalA.CaanB.MichaelsonR.VinciguerraV.Del PreteS.WinklerM.HallR.SimonM.WintersB. L.ElashoffR. M.Dietary fat reduction and breast cancer outcome: interim efficacy results from the women's intervention nutrition study20069824176717762-s2.0-3384589494610.1093/jnci/djj494ConnollyJ. M.GilhoolyE. M.RoseD. P.Effects of reduced dietary linoleic acid intake, alone or combined with an algal source of docosahexaenoic acid, on MDA-MB-231 breast cancer cell growth and apoptosis in nude mice199935144492-s2.0-0032786257NoguchiM.TaniyaT.KumakiT.Dietary fat and breast cancer: a controversial issue1997426775RoseD. P.ConnollyJ. M.Omega-3 fatty acids as cancer chemopreventive agents19998332172442-s2.0-003286056010.1016/S0163-7258(99)00026-1WuM.HarveyK. A.RuzmetovN.WelchZ. R.SechL.JacksonK.StillwellW.ZalogaG. P.SiddiquiR. A.Omega-3 polyunsaturated fatty acids attenuate breast cancer growth through activation of a neutral sphingomyelinase-mediated pathway200511733403482-s2.0-2644458558010.1002/ijc.21238ChajesV.SattlerW.StranzlA.KostnerG. M.Influence of n-3 fatty acids on the growth of human breast cancer cells in vitro: relationship to peroxides and vitamin-E19953431992122-s2.0-0028946787GrammatikosS. I.SubbaiahP. V.VictorT. A.MillerW. M.n-3 and n-6 fatty acid processing and growth effects in neoplastic and non-cancerous human mammary epithelial cell lines19947022192272-s2.0-0028017856SchleyP. D.JijonH. B.RobinsonL. E.FieldC. J.Mechanisms of omega-3 fatty acid-induced growth inhibition in MDA-MB-231 human breast cancer cells20059221871952-s2.0-2164446273010.1007/s10549-005-2415-zBarascuA.BessonP.Le FlochO.BougnouxP.JourdanM. L.CDK1-cyclin B1 mediates the inhibition of proliferation induced by omega-3 fatty acids in MDA-MB-231 breast cancer cells20063821962082-s2.0-2774444772910.1016/j.biocel.2005.08.015BlanckaertV.UlmannL.MimouniV.AntolJ.BrancquartL.ChénaisB.Docosahexaenoic acid intake decreases proliferation, increases apoptosis and decreases the invasive potential of the human breast carcinoma cell line MDA-MB-23120103637377422-s2.0-7714914582510.3892/ijo-00000549ChamrasH.ArdashianA.HeberD.GlaspyJ. A.Fatty acid modulation of MCF-7 human breast cancer cell proliferation, apoptosis and differentiation200213127117162-s2.0-003690536010.1016/S0955-2863(02)00230-9CorsettoP. A.MontorfanoG.ZavaS.JovenittiI. E.CremonaA.RizzoA. M.Effects of n-3 PUFAs on breast cancer cells through their incorporation in plasma membrane201110, article 732-s2.0-7995583083710.1186/1476-511X-10-73JudéS.RogerS.MartelE.BessonP.RichardS.BougnouxP.ChamperouxP.Le GuennecJ. Y.Dietary long-chain omega-3 fatty acids of marine origin: a comparison of their protective effects on coronary heart disease and breast cancers2006901–32993252-s2.0-2834445022410.1016/j.pbiomolbio.2005.05.006SantenR. J.SongR. X.McPhersonR.KumarR.AdamL.JengM. H.YueW.The role of mitogen-activated protein (MAP) kinase in breast cancer20028022392562-s2.0-003612806810.1016/S0960-0760(01)00189-3McCubreyJ. A.SteelmanL. S.ChappellW. H.AbramsS. L.WongE. W. T.ChangF.LehmannB.TerrianD. M.MilellaM.TafuriA.StivalaF.LibraM.BaseckeJ.EvangelistiC.MartelliA. M.FranklinR. A.Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance200717738126312842-s2.0-3454720934310.1016/j.bbamcr.2006.10.001SunH.BerquinI. M.OwensR. T.O'FlahertyJ. T.EdwardsI. J.Peroxisome proliferator-activated receptor γ-mediated up-regulation of syndecan-1 by n-3 fatty acids promotes apoptosis of human breast cancer cells2008688291229192-s2.0-4234911477510.1158/0008-5472.CAN-07-2305SunH.HuY.GuZ.OwensR. T.ChenY. Q.EdwardsI. J.Omega-3 fatty acids induce apoptosis in human breast cancer cells and mouse mammary tissue through syndecan-1 inhibition of the MEK-Erk pathway2011321015181524CalvielloG.PalozzaP.FranceschelliP.BartoliG. M.Low-dose eicosapentaenoic or docosahexaenoic acid administration modifies fatty acid composition and does not affect susceptibility to oxidative stress in rat erythrocytes and tissues19973210107510832-s2.0-003080873510.1007/s11745-997-0139-4HammamiehR.SumaidaD.ZhangX. Y.DasR.JettM.Control of the growth of human breast cancer cells in culture by manipulation of arachidonate metabolism20077, article 1382-s2.0-3454784349510.1186/1471-2407-7-138KangK. S.WangP.YamabeN.FukuiM.JayT.ZhuB. T.Docosahexaenoic acid induces apoptosis in MCF-7 cells in vitro and in vivo via reactive oxygen species formation and caspase 8 activation2010542-s2.0-77956395707e10296KikawaK. D.HerrickJ. S.TateoR. E.MouradianM.TayJ. S.PardiniR. S.Induced oxidative stress and cell death in the A549 lung adenocarcinoma cell line by ionizing radiation is enhanced by supplementation with docosahexaenoic acid2010628101710242-s2.0-7824924743010.1080/01635581.2010.492084LeonardiF.AttorriL.Di BenedettoR.Di BiaseA.SanchezM.NardiniM.SalvatiS.Effect of arachidonic, eicosapentaenoic and docosahexaenoic acids on the oxidative status of C6 glioma cells20053988658742-s2.0-2214445837510.1080/10715760500145069LindskogM.GleissmanH.PonthanF.CastroJ.KognerP.JohnsenJ. I.Neuroblastoma cell death in response to docosahexaenoic acid: sensitization to chemotherapy and arsenic-induced oxidative stress200611810258425932-s2.0-3364639677710.1002/ijc.21555MerendinoN.LoppiB.D'AquinoM.MolinariR.PessinaG.RomanoC.VelottiF.Docosahexaenoic acid induces apoptosis in the human PaCa-44 pancreatic cancer cell line by active reduced glutathione extrusion and lipid peroxidation20055222252332-s2.0-2764452202910.1207/s15327914nc5202_12SawC. L. L.HuangY.KongA. N.Synergistic anti-inflammatory effects of low doses of curcumin in combination with polyunsaturated fatty acids: docosahexaenoic acid or eicosapentaenoic acid20107934214302-s2.0-7044965777010.1016/j.bcp.2009.08.030VibetS.GoupilleC.BougnouxP.SteghensJ. P.GoréJ.MahéoK.Sensitization by docosahexaenoic acid (DHA) of breast cancer cells to anthracyclines through loss of glutathione peroxidase (GPx1) response2008447148314912-s2.0-4104909377310.1016/j.freeradbiomed.2008.01.009SiddiquiR. A.HarveyK.StillwellW.Anticancer properties of oxidation products of docosahexaenoic acid2008153147562-s2.0-4304917047410.1016/j.chemphyslip.2008.02.009SunH.HuY.GuZ.WilsonM. D.ChenY. Q.RudelL. L.WillinghamM. C.EdwardsI. J.Endogenous synthesis of n-3 polyunsaturated fatty acids in Fat-1 mice is associated with increased mammary gland and liver syndecan-12011652-s2.0-7995779469510.1371/journal.pone.0020502e20502ChapkinR. S.McmurrayD. N.DavidsonL. A.PatilB. S.FanY. Y.LuptonJ. R.Bioactive dietary long-chain fatty acids: emerging mechanisms of action20081006115211572-s2.0-5634910953210.1017/S0007114508992576Aliche-DjoudiF.PodechardN.ChevanneM.Physical and chemical modulation of lipid rafts by a dietary n-3 polyunsaturated fatty acid increases ethanol-induced oxidative stress201151112018203010.1016/j.freeradbiomed.2011.08.031CalderP. C.Fatty acids and inflammation: the cutting edge between food and pharma2011668supplement 1S50S582-s2.0-7996089130910.1016/j.ejphar.2011.05.085CorsettoP. A.CremonaA.MontorfanoG.Chemical-physical changes in cell membrane microdomains of breast cancer cells after omega-3 PUFA incorporationCell Biochemistry and Biophysics. In press10.1007/s12013-012-9365-yShaikhS. R.LoCascioD. S.SoniS. P.WassallS. R.StillwellW.Oleic- and docosahexaenoic acid-containing phosphatidylethanolamines differentially phase separate from sphingomyelin2009178811242124262-s2.0-7114909186110.1016/j.bbamem.2009.08.019YeS.TanL.MaJ.ShiQ.LiJ.Polyunsaturated docosahexaenoic acid suppresses oxidative stress induced endothelial cell calcium influx by altering lipid composition in membrane caveolar rafts201083137432-s2.0-7795353423010.1016/j.plefa.2010.02.002WassallS. R.StillwellW.Docosahexaenoic acid domains: the ultimate non-raft membrane domain2008153157632-s2.0-4304917047310.1016/j.chemphyslip.2008.02.010WassallS. R.StillwellW.Polyunsaturated fatty acid-cholesterol interactions: domain formation in membranes20091788124322-s2.0-5814920226710.1016/j.bbamem.2008.10.011SiddiquiR. A.HarveyK. A.ZalogaG. P.StillwellW.Modulation of lipid rafts by omega-3 fatty acids in inflammation and cancer: implications for use of lipids during nutrition support200722174882-s2.0-3384663040410.1177/011542650702200174LiQ.ZhangQ.WangM.LiuF.ZhaoS.MaJ.LuoN.LiN.LiY.XuG.LiJ.Docosahexaenoic acid affects endothelial nitric oxide synthase in caveolae200746622502592-s2.0-3454879107110.1016/j.abb.2007.06.023LiQ.ZhangQ.WangM.ZhaoS.XuG.LiJ.n-3 polyunsaturated fatty acids prevent disruption of epithelial barrier function induced by proinflammatory cytokines2008455135613652-s2.0-3734911760410.1016/j.molimm.2007.09.003AltenburgJ. D.SiddiquiR. A.Omega-3 polyunsaturated fatty acids down-modulate CXCR4 expression and function in MDA-MB-231 breast cancer cells200977101310202-s2.0-6765116051610.1158/1541-7786.MCR-08-0385SchleyP. D.BrindleyD. N.FieldC. J.(n-3) PUFA alter raft lipid composition and decrease epidermal growth factor receptor levels in lipid rafts of human breast cancer cells200713735485532-s2.0-33947169954ImE.MartinezJ. D.Ursodeoxycholic acid (UDCA) can inhibit deoxycholic acid (DCA)-induced apoptosis via modulation of EGFR/Raf-1/ERK signaling in human colon cancer cells200413424834862-s2.0-0942301272QiuL.ZhouC.SunY.DiW.SchefflerE.HealeyS.WaneboH.KouttabN.ChuW.WanY.Paclitaxel and ceramide synergistically induce cell death with transient activation of EGFR and ERK pathway in pancreatic cancer cells20061649079132-s2.0-34547619923SquiresM. S.HudsonE. A.HowellsL.SaleS.HoughtonC. E.JonesJ. L.FoxL. H.DickensM.PrigentS. A.MansonM. M.Relevance of mitogen activated protein kinase (MAPK) and phosphotidylinositol-3-kinase/protein kinase B (PI3K/PKB) pathways to induction of apoptosis by curcumin in breast cells20036533613762-s2.0-003729979910.1016/S0006-2952(02)01517-4CuadradoA.García-FernándezL. F.GonzálezL.SuárezY.LosadaA.AlcaideV.MartínezT.Máa Fernández-SousaJ.Sánchez-PuellesJ. M.MuñozA.Aplidin induces apoptosis in human cancer cells via glutathione depletion and sustained activation of the epidermal growth factor receptor, Src, JNK, and p38 MAPK200327812412502-s2.0-034603609310.1074/jbc.M201010200RogersK. R.KikawaK. D.MouradianM.HernandezK.McKinnonK. M.AhwahS. M.PardiniR. S.Docosahexaenoic acid alters epidermal growth factor receptor-related signaling by disrupting its lipid raft association2010319152315302-s2.0-7795629553210.1093/carcin/bgq111Dimanche-BoitrelM. T.RebillardA.GulbinsE.Ceramide in chemotherapy of tumors201163284293FuruyaH.ShimizuY.KawamoriT.Sphingolipids in cancer2011303-4567576LafontE.KitataniK.OkazakiT.SeguiB.Regulation of death and growth signals at the plasma membrane by sphingomyelin synthesis: implications for hematological malignancies201163324333Nikolova-KarakashianM. N.RozenovaK. A.Ceramide in stress response2010688861082-s2.0-7804950469810.1007/978-1-4419-6741-1_6RaghuH.SodadasuP. K.MallaR. R.GondiC. S.EstesN.RaoJ. S.Localization of uPAR and MMP-9 in lipid rafts is critical for migration, invasion and angiogenesis in human breast cancer cells201010, article 6472-s2.0-7854926915310.1186/1471-2407-10-647GilletL.RogerS.BougnouxP.Le GuennecJ. Y.BessonP.Beneficial effects of omega-3 long-chain fatty acids in breast cancer and cardiovascular diseases: voltage-gated sodium channels as a common feature?2011931462-s2.0-7864995628110.1016/j.biochi.2010.02.005IsbilenB.FraserS. P.DjamgozM. B. A.Docosahexaenoic acid (omega-3) blocks voltage-gated sodium channel activity and migration of MDA-MB-231 human breast cancer cells20063812217321822-s2.0-3374880548210.1016/j.biocel.2006.06.014MaguyA.HebertT. E.NattelS.Involvement of lipid rafts and caveolae in cardiac ion channel function20066947988072-s2.0-3244444714410.1016/j.cardiores.2005.11.013HillerD.ChuQ. D.CXCR4 and axillary lymph nodes: review of a potential biomarker for breast cancer metastasis20112011642098110.4061/2011/420981DewanM. Z.AhmedS.IwasakiY.OhbaK.ToiM.YamamotoN.Stromal cell-derived factor-1 and CXCR4 receptor interaction in tumor growth and metastasis of breast cancer20066062732762-s2.0-3374710908610.1016/j.biopha.2006.06.004MüllerA.HomeyB.SotoH.GeN.CatronD.BuchananM. E.McClanahanT.MurphyE.YuanW.WagnerS. N.BarreraJ. L.MoharA.VerásteguiE.ZlotnikA.Involvement of chemokine receptors in breast cancer metastasis2001410682450562-s2.0-003528243210.1038/35065016ChenX.BeutlerJ. A.McCloudT. G.LoehfelmA.YangL.DongH. F.ChertovO. Y.SalcedoR.OppenheimJ. J.HowardO. M. Z.Tannic acid is an inhibitor of CXCL12 (SDF-1α)/CXCR4 with antiangiogenic activity200398311531232-s2.0-12444311670FernandisA. Z.PrasadA.BandH.KlöselR.GanjuR. K.Regulation of CXCR4-mediated chemotaxis and chemoinvasion of breast cancer cells20042311571672-s2.0-094230117210.1038/sj.onc.1206910KangH.WatkinsG.ParrC.Douglas-JonesA.ManselR. E.JiangW. G.Stromal cell derived factor-1: its influence on invasiveness and migration of breast cancer cells in vitro, and its association with prognosis and survival in human breast cancer200574R402R4102-s2.0-33644789290ChajèsV.MahonM.KostnerG. M.Influence of LDL oxidation on the proliferation of human breast cancer cells19962011131202-s2.0-003002385710.1016/0891-5849(95)02013-6HardyS.El-AssaadW.PrzybytkowskiE.JolyE.PrentkiM.LangelierY.Saturated fatty acid-induced apoptosis in MDA-MB-231 breast cancer cells. A role for cardiolipin20032783431861318702-s2.0-004135531510.1074/jbc.M300190200RothenederM.KostnerG. M.Effects of low- and high-density lipoproteins on the proliferation of human breast cancer cells in vitro: differences between hormone-dependent and hormone-independent cell lines19894358758792-s2.0-0024361441AntalisC. J.ArnoldT.RasoolT.LeeB.BuhmanK. K.SiddiquiR. A.High ACAT1 expression in estrogen receptor negative basal-like breast cancer cells is associated with LDL-induced proliferation201012236616702-s2.0-7795555502510.1007/s10549-009-0594-8NeveR. M.ChinK.FridlyandJ.A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes2006106515527FarmerP.BonnefoiH.BecetteV.Tubiana-HulinM.FumoleauP.LarsimontD.MacGroganG.BerghJ.CameronD.GoldsteinD.DussS.NicoulazA. L.BriskenC.FicheM.DelorenziM.IggoR.Identification of molecular apocrine breast tumours by microarray analysis20052429466046712-s2.0-2274444886410.1038/sj.onc.1208561RichardsonA. L.WangZ. C.de NicoloA.LuX.BrownM.MironA.LiaoX.IglehartJ. D.LivingstonD. M.GanesanS.X chromosomal abnormalities in basal-like human breast cancer2006921211322-s2.0-3204445334310.1016/j.ccr.2006.01.013van de VijverM. J.HeY. D.van'T VeerL. J.DaiH.HartA. A. M.VoskuilD. W.SchreiberG. J.PeterseJ. L.RobertsC.MartonM. J.ParrishM.AtsmaD.WitteveenA.GlasA.DelahayeL.van der VeldeT.BartelinkH.RodenhuisS.RutgersE. T.FriendS. H.BernardsR.A gene-expression signature as a predictor of survival in breast cancer200234725199920092-s2.0-003713751910.1056/NEJMoa021967van't VeerL. J.DaiH.van de VijverM. J.HeY. D.HartA. A. M.MaoM.PeterseH. L.van der KooyK.MartonM. J.WitteveenA. T.SchreiberG. J.KerkhovenR. M.RobertsC.LinsleyP. S.BernardsR.FriendS. H.Gene expression profiling predicts clinical outcome of breast cancer200241568715305362-s2.0-1824440968710.1038/415530aAntalisC. J.UchidaA.BuhmanK. K.SiddiquiR. A.Migration of MDA-MB-231 breast cancer cells depends on the availability of exogenous lipids and cholesterol esterification20112887337412-s2.0-7995999639510.1007/s10585-011-9405-9ChangN. W.WuC. T.RC. D.YehC. Y.LinC.High levels of arachidonic acid and peroxisome proliferator-activated receptor-alpha in breast cancer tissues are associated with promoting cancer cell proliferationJournal of Nutritional Biochemistry. In pressHietanenE.PunnonenK.PunnonenR.AuvinenO.Fatty acid composition of phospholipids and neutral lipids and lipid peroxidation in human breast cancer and lipoma tissue1986712196519692-s2.0-002298884310.1093/carcin/7.12.1965MaillardV.BougnouxP.FerrariP.JourdanM. L.PinaultM.LavillonnìreF.BodyG.Le FlochO.ChajèsV.n-3 and n-6 fatty acids in breast adipose tissue and relative risk of breast cancer in a case-control study in tours, France200298178832-s2.0-003649802410.1002/ijc.10130RayD. M.MyersP. H.PainterJ. T.HoenerhoffM. J.OldenK.RobertsJ. D.Inhibition of transforming growth factor-beta-activated kinase-1 blocks cancer cell adhesion, invasion, and metastasisBritish Journal of Cancer. In press10.1038/bjc.2012.214RayD. M.RogersB. A.SunmanJ. A.AkiyamaS. K.OldenK.RobertsJ. D.Lysine 63-linked ubiquitination is important for arachidonic acid-induced cellular adhesion and migration20108869479562-s2.0-7865038246610.1139/O10-148Villegas-ComonfortS.Serna-MarquezN.Galindo-HernandezO.Navarro-TitoN.SalazarE. P.Arachidonic acid induces an increase of beta-1,4-galactosyltransferase I expression in MDA-MB-231 breast cancer cellsJournal of Cellular Biochemistry. In pressWenZ. H.SuY. C.LaiP. L.Critical role of arachidonic acid-activated mTOR signaling in breast carcinogenesis andangiogenesisOncogene. In press10.1038/onc.2012.47MalobertiP. M.DuarteA. B.OrlandoU. D.PasqualiniM. E.SolanoA. R.Lopez-OtínC.PodestaE. J.Functional interaction between acyl-coa synthetase 4, lipooxygenases and cyclooxygenase-2 in the aggressive phenotype of breast cancer cells20105112-s2.0-7864973793210.1371/journal.pone.0015540e15540ByonC. H.HardyR. W.RenC.PonnazhaganS.WelchD. R.McDonaldJ. M.ChenY.Free fatty acids enhance breast cancer cell migration through plasminogen activator inhibitor-1 and SMAD420098911122112282-s2.0-7035068104710.1038/labinvest.2009.97ReyesN.ReyesI.TiwariR.GeliebterJ.Effect of linoleic acid on proliferation and gene expression in the breast cancer cell line T47D2004209125352-s2.0-244251556310.1016/j.canlet.2003.12.010Espinosa-NeiraR.Mejia-RangelJ.Cortes-ReynosaP.SalazarE. P.Linoleic acid induces an EMT-like process in mammary epithelial cells MCF10A2011431217821791KelleyN. S.HubbardN. E.EricksonK. L.Conjugated linoleic acid isomers and cancer200713712259926072-s2.0-37149029741AmarùD. L.FieldC. J.Conjugated linoleic acid decreases MCF-7 human breast cancer cell growth and insulin-like growth factor-1 receptor levels20094454494582-s2.0-6734919426810.1007/s11745-009-3288-4IslamM. A.KimY. S.JangW. J.LeeS. M.KimH. G.KimS. Y.KimJ. O.HaY. L.A mixture of trans, trans conjugated linoleic acid induces apoptosis in MCF-7 human breast cancer cells with reciporocal expression of Bax and Bcl-220085614597059762-s2.0-4904910167110.1021/jf8004977WangL. S.HuangY. W.LiuS.YanP.LinY. C.Conjugated linoleic acid induces apoptosis through estrogen receptor alpha in human breast tissue20088, article 2082-s2.0-5014910985210.1186/1471-2407-8-208MigliettaA.BozzoF.BoccaC.GabrielL.TrombettaA.BelottiS.CanutoR. A.Conjugated linoleic acid induces apoptosis in MDA-MB-231 breast cancer cells through ERK/MAPK signalling and mitochondrial pathway200623421491572-s2.0-3364500364410.1016/j.canlet.2005.03.029BoccaC.BozzoF.CannitoS.ColombattoS.MigliettaA.CLA reduces breast cancer cell growth and invasion through ERα and PI3K/Akt pathways201018311871932-s2.0-7134908846310.1016/j.cbi.2009.09.022BoccaC.BozzoF.FrancicaS.ColombattoS.MigliettaA.Involvement of PPARγ and E-cadherin/β-catenin pathway in the antiproliferative effect of conjugated linoleic acid in MCF-7 cells200712122482562-s2.0-3425037688310.1002/ijc.22646HuotP. S. P.SarkarB.MaD. W. L.Conjugated linoleic acid alters caveolae phospholipid fatty acid composition and decreases caveolin-1 expression in MCF-7 breast cancer cells20103031791852-s2.0-7795225129310.1016/j.nutres.2010.02.003FayM. P.FreedmanL. S.Meta-analyses of dietary fats and mammary neoplasms in rodent experiments1997462-32152232-s2.0-003144483610.1023/A:1005927503865IpC.Review of the effects of trans fatty acids, oleic acid, n-3 polyunsaturated fatty acids, and conjugated linoleic acid on mammary carcinogenesis in animals1997666, supplement1523S1529S2-s2.0-0030686589RoseD. P.Effects of dietary fatty acids on breast and prostate cancers: evidence from in vitro experiments and animal studies1997666, supplement1513S1522S2-s2.0-0030692082WadaM.DeLongC. J.HongY. H.RiekeC. J.SongI.SidhuR. S.YuanC.WarnockM.SchmaierA. H.YokoyamaC.SmythE. M.WilsonS. J.FitzGeraldG. A.GaravitoR. M.DeX. S.ReganJ. W.SmithW. L.Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates and products20072823122254222662-s2.0-3454795861510.1074/jbc.M703169200BaggaD.AndersK. H.WangH. J.GlaspyJ. A.Long-chain n-3-to-n-6 polyunsaturated fatty acid ratios in breast adipose tissue from women with and without breast cancer20024221801852-s2.0-0036035977MurffH. J.ShuX. O.LiH.YangG.WuX.CaiH.WenW.GaoY. T.ZhengW.Dietary polyunsaturated fatty acids and breast cancer risk in Chinese women: a prospective cohort study20111286143414412-s2.0-7955146966510.1002/ijc.25703Gago-DominguezM.YuanJ. M.SunC. L.LeeH. P.YuM. C.Opposing effects of dietary n-3 and n-6 fatty acids on mammary carcinogenesis: the Singapore Chinese health study2003899168616922-s2.0-034444098410.1038/sj.bjc.6601340Bernard-GallonD. J.Vissac-SabatierC.Antoine-VincentD.RioP. G.MaurizisJ. C.FustierP.BignonY. J.Differential effects of n-3 and n-6 polyunsaturated fatty acids on BRCA1 and BRCA2 gene expression in breast cell lines20028742812892-s2.0-003622785210.1079/BJNBJN2002522BougnouxP.HajjajiN.FerrassonM. N.GiraudeauB.CouetC.Le FlochO.Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial200910112197819852-s2.0-7164909322010.1038/sj.bjc.6605441BougnouxP.HajjajiN.MaheoK.CouetC.ChevalierS.Fatty acids and breast cancer: sensitization to treatments and prevention of metastatic re-growth201049176862-s2.0-7174910627310.1016/j.plipres.2009.08.003AltenburgJ. D.BieberichA. A.TerryC.HarveyK. A.VanHornJ. F.XuZ.Jo DavissonV.SiddiquiR. A.A synergistic antiproliferation effect of curcumin and docosahexaenoic acid in SK-BR-3 breast cancer cells: unique signaling not explained by the effects of either compound alone201111, article 1492-s2.0-7995457870710.1186/1471-2407-11-149SiddiquiR. A.HarveyK. A.XuZ.BammerlinE. M.WalkerC.AltenburgJ. D.Docosahexaenoic acid: a natural powerful adjuvant that improves efficacy for anticancer treatment with no adverse effects201137639941210.1002/biof.181