Breast Cancer Research and Treatment

, Volume 92, Issue 2, pp 187–195 | Cite as

Mechanisms of omega-3 fatty acid-induced growth inhibition in MDA-MB-231 human breast cancer cells

  • Patricia D. Schley
  • Humberto B. Jijon
  • Lindsay E. Robinson
  • Catherine J. FieldEmail author


The omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), inhibit the growth of human breast cancer cells in animal models and cell lines, but the mechanism by which this occurs is not well understood. In order to explore possible mechanisms for the modulation of breast cancer cell growth by omega-3 fatty acids, we examined the effects of EPA and DHA on the human breast cancer cell line MDA-MB-231. Omega-3 fatty acids (a combination of EPA and DHA) inhibited the growth of MDA-MB-231 cells by 30–40% (p<0.05) in both the presence and absence of linoleic acid, an essential omega-6 fatty acid. When provided individually, DHA was more potent than EPA in inhibiting the growth of MDA-MB-231 cells (p<0.05). EPA and DHA treatment decreased tumor cell proliferation (p<0.05), as estimated by decreased [methyl−3H]-thymidine uptake and expression of proliferation-associated proteins (proliferating cell nuclear antigen, PCNA, and proliferation-related kinase, PRK). In addition, EPA and DHA induced apoptosis, as indicated by a loss of mitochondrial membrane potential, increased caspase activity and increased DNA fragmentation (p<0.05). Cells incubated with omega-3 fatty acids demonstrated decreased Akt phosphorylation, as well as NFκB DNA binding activity (p<0.05). The results of this study indicate that omega-3 fatty acids decrease cell proliferation and induce apoptotic cell death in human breast cancer cells, possibly by decreasing signal transduction through the Akt/NFκB cell survival pathway.


Akt apoptosis breast cancer docosahexaenoic acid eicosapentaenoic acid MDA-MB-231 NFκB omega-3 fatty acid proliferation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Deckere, EAM 1999Possible beneficial effect of fish and fish n-3 polyunsaturated fatty acids in breast and colorectal cancerEur J␣Cancer Prev8213221Google Scholar
  2. 2.
    Rose, DP, Connolly, JM 1999Omega-3 fatty acids as cancer chemopreventive agentsPharmacol Ther83217244Google Scholar
  3. 3.
    Begin, ME, Ells, G, Das, UN, Horrobin, DF 1986Differential killing of human carcinoma cells supplemented with n-3 and n-6 polyunsaturated fatty acidsJ Natl Cancer Inst7710531061Google Scholar
  4. 4.
    Begin, ME, Ells, G, Horrobin, DF 1988Polyunsaturated fatty acid-induced cytotoxicity against tumor cells and its relationship to lipid peroxidationJ Natl Cancer Inst80188194Google Scholar
  5. 5.
    Rose, DP, Connolly, JM 1990Effects of fatty acids and inhibitors of eicosanoid synthesis on the growth of a human breast cancer cell line in cultureCancer Res5071397144Google Scholar
  6. 6.
    Grammatikos, SI, Subbaiah, PV, Victor, TA, Miller, WM 1994n-3 and n-6 fatty acid processing and growth effects in neoplastic and non-cancerous human mammary epithelial cell linesBr J Cancer70219227Google Scholar
  7. 7.
    Chajes, V, Sattler, W, Stranzl, A, Kostner, GM 1995Influence of n-3 fatty acids on the growth of human breast cancer cells in vitro: relationship to peroxides and vitamin-EBreast Cancer Res Treat34199212Google Scholar
  8. 8.
    Noguchi, M, Earashi, M, Minami, M, Kinoshita, K, Miyazaki, I 1995Effects of eicosapentaenoic and docosahexaenoic acid on cell growth and prostaglandin E and leukotriene B production by a human breast cancer cell line (MDA-MB-231)Oncology52458464Google Scholar
  9. 9.
    Abdi-Dezfuli, F, Froyland, L, Thorsen, T, Aakvaag, A, Berge, RK 1997Eicosapentaenoic acid and sulphur substituted fatty acid analogues inhibit the proliferation of human breast cancer cells in cultureBreast Cancer Res Treat45229239Google Scholar
  10. 10.
    Senzaki, H, Iwamoto, S, Ogura, E, Kiyozuka, Y, Arita, S, Kurebayashi, J, Takada, H, Hioki, K, Tsubura, A 1998Dietary effects of fatty acids on growth and metastasis of KPL-1 human breast cancer cells in vivo and in vitroAnticancer Res1816211628Google Scholar
  11. 11.
    Yamamoto, D, Kiyozuka, Y, Adachi, Y, Takada, H, Hioki, K, Tsubura, A 1999Synergistic action of apoptosis induced by eicosapentaenoic acid and TNP-470 on human breast cancer cellsBreast Cancer Res Treat55149160Google Scholar
  12. 12.
    Chamras, H, Ardashian, A, Heber, D, Glaspy, JA 2002Fatty acid modulation of MCF-7 human breast cancer cell proliferation, apoptosis and differentiationJ Nutr Biochem13711716Google Scholar
  13. 13.
    Ip, C, Carter, CA, Ip, MM 1985Requirement of essential fatty acid for mammary tumorigenesis in the ratCancer Res4519972001Google Scholar
  14. 14.
    Nicholson, KM, Anderson, NG 2002The protein kinase B/Akt signalling pathway in human malignancyCell Signal14381395Google Scholar
  15. 15.
    Vivanco, I, Sawyers, CL 2002The phosphatidylinositol 3-kinase-Akt pathway in human cancerNat Rev Cancer2489501Google Scholar
  16. 16.
    Nakshatri, H, Bhat-Nakshatri, P, Martin, DA, Goulet, RJ,Jr, Sledge, GW,Jr 1997 Constitutive activation of NF-κB during progression of breast cancer to hormone-independent growthMol Cell Biol1736293639Google Scholar
  17. 17.
    Ma, DWL, Wierzbicki, AA, Field, CJ, Clandinin, MT 1999Preparation of conjugated linoleic acid from safflower oilJ Am Oil Chem Soc76729730Google Scholar
  18. 18.
    Jijon, HB, Panenka, WJ, Madsen, KL, Parsons, HG 2002MAP kinases contribute to IL-8 secretion by intestinal epithelial cells via a posttranscriptional mechanismAm J Physiol Cell Physiol283C31C41Google Scholar
  19. 19.
    Ma, DWL, Field, CJ, Clandinin, MT 2002An enriched mixture of trans-10, cis-12-CLA inhibits linoleic acid metabolism and PGE2 synthesis in MDA-MB-231 cellsNutr Cancer44202212Google Scholar
  20. 20.
    Kachhap, SK, Dange, PP, Santani, RH, Sawant, SS, Ghosh, SN 2001Effect of ω-3 fatty acid (docosahexaenoic acid) on BRCA1 gene expression and growth in MCF-7 cell lineCancer Biother Radiopharm16257263Google Scholar
  21. 21.
    Begin, ME, Das, UN, Ells, G, Horrobin, DF 1985Selective killing of human cancer cells by polyunsaturated fatty acidsProstaglandins Leukot Med19177186Google Scholar
  22. 22.
    Gabor, H, Abraham, S 1986Effect of dietary menhaden oil on tumor cell loss and the accumulation of mass of a transplantable mammary adenocarcinoma in BALB/c miceJ Natl Cancer Inst7612231229Google Scholar
  23. 23.
    Istfan, NW, Wan, J, Chen, Z-Y 1995Fish oil and cell proliferation kinetics in a mammary carcinoma tumor modelAdv Exp Med Biol375149156Google Scholar
  24. 24.
    Connolly, JM, Gilhooly, EM, Rose, DP 1999Effects 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 miceNutr Cancer354449Google Scholar
  25. 25.
    Graffenried, LA, Friedrichs, WE, Fulcher, L, Fernandes, G, Silva, JM, Peralba, J-M, Hidalgo, M 2003Eicosapentaenoic acid restores tamoxifen sensitivity in breast cancer cells with high Akt activityAnn Oncol1410511056Google Scholar
  26. 26.
    Jurkowski, JJ, Cave, WTJ 1985Dietary effects of menhaden oil on the growth and membrane lipid composition of rat mammary tumorsJ Natl Cancer Inst7411451150Google Scholar
  27. 27.
    Karmali, RA, Donner, A, Gobel, S, Shimamura, T 1989Effect of n-3 and n-6 fatty acids on 7,12 Dimethylbenz (a) anthracene-induced mammary tumorigenesisAnticancer Res911611168Google Scholar
  28. 28.
    Rose, DP, Connolly, JM, Rayburn, J, Coleman, M 1995Influence of diets containing eicosapentaenoic or docosahexaenoic acid on growth and metastasis of breast cancer cell in nude miceJ Natl Cancer Inst87587592Google Scholar
  29. 29.
    Lee, JY, Ye, J, Gao, Z, Youn, HS, Lee, WH, Zhao, L, Sizemore, N, Hwang, DH 2003Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acidsJ Biol Chem2783704137051Google Scholar
  30. 30.
    Lee, JY, Zhao, L, Youn, HS, Weatherill, AR, Tapping, R, Feng, L, Lee, WH, Fitzgerald, KA, Hwang, DH 2004Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1J Biol Chem2791697116979Google Scholar
  31. 31.
    Zhao, Y, Joshi-Barve, S, Barve, S, Chen, LH 2004Eicosapentaenoic acid prevents LPS-induced TNF-alpha expression by preventing NF-kappaB activationJ Am Coll Nutr237178Google Scholar
  32. 32.
    Novak, TE, Babcock, TA, Jho, DH, Helton, WS, Espat, NJ 2003NF-kappa B inhibition by omega-3 fatty acids modulates LPS-stimulated macrophage TNF-alpha transcriptionAm J Physiol Lung Cell Mol Physiol284L84L89Google Scholar
  33. 33.
    Sovak, MA, Bellas, RE, Kim, DW, Zanieski, GJ, Rogers, AE, Traish, AM 1997Aberrant nuclear factor-κB/Rel expression and the pathogenesis of breast cancerJ Clin Invest10029522960Google Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Patricia D. Schley
    • 1
  • Humberto B. Jijon
    • 2
  • Lindsay E. Robinson
    • 3
  • Catherine J. Field
    • 1
    • 4
    Email author
  1. 1.Department of Agricultural,Food and Nutritional ScienceUniversity of AlbertaAlbertaCanada
  2. 2.Department of MedicineDivision of Gastroenterology, University of AlbertaAlbertaCanada
  3. 3.Department of Human Biology and Nutritional SciencesUniversity of GuelphOntarioCanada
  4. 4.Department of AgriculturalFood and Nutritional Science, University of Alberta,AlbertaCanada

Personalised recommendations