Skip to main content
SpringerLink
Log in

Influence of n-3 fatty acids on the growth of human breast cancer cellsin vitro: Relationship to peroxides and Vitamin-E

  • Report
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Epidemiological studies suggest a causal relationship of dietary polyunsaturated fatty acids (PUFA's) with the morbidity and mortality from breast cancer. In order to reveal possible underlying mechanisms of these findings, we studied the influence of n-3 and n-6 PUFA's in comparison to oleic acid on the proliferation of well characterized estrogen dependent (MCF-7, ZR-75, T-47-D) and estrogen independent (MDA-MB-231, HBL-100) breast cancer cells in culture. The cell growth inhibitory effect was related to the formation of lipid peroxidation products. Normal human skin fibroblasts served as a control. In fibroblasts, the addition of 20 µg/ml of exogenous fatty acids either had no effect or caused an insignificant increase of proliferation. Similar results were obtained with MCF-7 cells. In all other breast cancer cell types, n-3 long-chain PUFA's, eicosapentaenoic and docosahexaenoic acids, were the most effective fatty acids in arresting the cell growth. Alpha-linolenic and gamma-linolenic acid exerted a variable effect on cell proliferation depending on the cell line investigated. Oleic acid significantly stimulated the proliferation of hormone-independent breast cancer cells while it had no effect on the proliferation of hormone-dependent cells. Viability studies by trypan blue excretion indicated that the arrest in cell growth was not due to major cytotoxic effects.

The addition of PUFA's to breast cancer cells caused a significant increase in the formation of conjugated dienes and lipid hydroperoxides in the cellular lipids; their content was significantly correlated with the capacity of arresting cell growth. In contrast, the addition of PUFA's to fibroblasts did not increase lipid hydroperoxide formation. The addition of Vitamin E to cancer cells at a concentration of 10 µM to the PUFA-supplemented medium almost completely restored cell growth.

Our data indicate that PUFA's significantly interfere with cell proliferation of breast cancer cellsin vitro due to the formation of oxidation products. In addition to that, there must be other factors involved, most probably related to the differential metabolism of PUFA's in tumor cells. Our findings may have some impact on treatment and prevention of breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abbreviations

ALA:

Alpha-Linolenic Acid

GLA:

Gamma-Linolenic Acid

DHA:

Docosahexaenoic Acid

EPA:

Eicosapentaenoic Acid

ER:

Estrogen Receptor

OA:

Oleic Acid

PUFA's:

Polyunsaturated Fatty Acids

References

  1. Galli C, Butrum R: Dietary ω3 fatty acids and cancer: An overview. In: Simopoulos AP, Kifer RR, Martin RE, Barlow SM (eds) Health effects of ε3 polyunsaturated fatty acids in seafoods. Basel: Karger, 1991, vol 66, pp. 446–461

    Google Scholar 

  2. Man-Fan Wan J, Kanders BS, Kowalchuk M, Knapp H, Szeluga DJ, Bagley J, Blackburn GL: ω3 fatty acids and cancer metastasis in humans. In: Simopoulos AP, Kifer RR, Martin RE, Barlow SM (eds) Health effects of ε3 polyunsaturated fatty acids in seafoods. Basel: Karger, 1991, vol 66, pp. 477–487

    Google Scholar 

  3. Stampfer MJ, Willett WC, Colditz GAet al.: Intake of cholesterol, fish and specific types of fat in relation to risk of breast cancer. In: Lands WEM (ed.) Polyunsaturated fatty acids and eicosanoids. Champaign, AOCS, 1987, pp. 248–252

    Google Scholar 

  4. Kaizer L, Boyd NF, Kriukov V, Tritchler D: Fish consumption and breast cancer risk: An ecological study. Nutr Cancer 12: 61–68, 1989

    Google Scholar 

  5. Dolececk TA, Grandits G: Dietary polyunsaturated fatty acids and mortality in the multiple risk factor intervention trial (MRFIT). In: Simopoulos AP, Kifer RR, Martin RE, Barlow SM (eds) Health effects of ω3 polyunsaturated fatty acids in seafoods. Basel: Karger, 1991, vol 66, pp. 205–216

    Google Scholar 

  6. Dolececk TA: Epidemiologic evidence of relationships between dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial. Proc Soc Exp Biol Med 200: 177–182, 1992

    Google Scholar 

  7. Cave WT: Dietary n-3 (ε3) polyunsaturated fatty acid effects on animal tumorigenesis. FASEB 5: 2160–2166, 1991

    Google Scholar 

  8. Fritsche KL, Johnston PV: Effect of dietary alpha-linolenic acid on growth, metastasis, fatty acid profile and prostaglandin production of two murine mammary adenocarcinomas. J Nutr 120: 1601–1609, 1990

    Google Scholar 

  9. Hirose M, Masuda A, Ito N, Kamano K, Okuyama H: Effects of dietary perilla oil, soybean oil and safflower oil on 7,12-dimethylbenz(a)anthracene (DMBA) and 1,2-dimethylhydrazine (DMH)-induced mammary gland and colon carcinogenesis in female SD rats. Carcinogenesis 11: 731–735, 1990

    Google Scholar 

  10. Kamano K, Okuyama H, Konishi R, Nagasawa H: Effects of a high-linoleate and a high-alpha-linolenate diet on spontaneous mammary tumorigenesis in mice. Anticancer Res 9: 1903–1908, 1989

    Google Scholar 

  11. Gonzalez MJ, Schemmel RA, Gray JI, Dugan L, Sheffield G, Welsch CW: Effect of dietary fat on growth of MCF-7 and MDA-MB 231 human breast carcinomas in athymic nude mice: relationship between carcinoma growth and lipid peroxidation product levels. Carcinogenesis 12: 1231–1235, 1991

    Google Scholar 

  12. Gonzalez MJ, Schemmel RA, Dugan L, Gray JI, Welsch CW: Dietary fish oil inhibits human breast carcinoma growth: a function of increased lipid peroxidation. Lipids 28: 827–832, 1993

    Google Scholar 

  13. Takeda S, Horrobin DF, Manku MS: The effects of gammalinolenic acid on human breast cancer cell killing, lipid peroxidation and the production of Schiff-reactive materials. Med Sci Res 20: 203–205, 1992

    Google Scholar 

  14. Takeda S, Horrobin DF, Manku M, Sim PG, Ells G, Simmons V: Lipid peroxidation in human breast cancer cells in response to gamma-linolenic acid and iron. Anticancer Res 12: 329–334, 1992

    Google Scholar 

  15. Takeda S, Sim PG, Horrobin DF, Chisholm KA, Simmons VA, Ells GW, Jenkins DK, Morse-Fisher NL: Intracellular free fatty acid release and lipid peroxidation in cultured human breast cancer cells in response to gamma-linolenic acid with iron (GLA + Fe). Int J Oncol 1: 759–763, 1992

    Google Scholar 

  16. Takeda S, Sim PG, Horrobin DF, Sanford T, Chisholm KA, Simmons V: Mechanism of lipid peroxidation in cancer cells in response to gamma-linolenic acid (GLA) analyzed by GC-MS (I): conjugated dienes with peroxyl (or hydroperoxyl) groups and cell-killing effects. Anticancer Res 13: 193–200, 1993

    Google Scholar 

  17. Cantrill RC, Ells G, Chisholm K, Horrobin DF: Concentration-dependent effect of iron on gamma-linolenic acid toxicity in ZR-75-1 human breast tumor cells in culture. Cancer Lett 72: 99–102, 1993

    Google Scholar 

  18. Rotheneder M, Kostner GM: Effects of low- and high-density lipoproteins on the proliferation of human breast cancer cellsin vitro: differences between hormone-dependent and hormone-independent cell lines. Int J Cancer 43: 875–879, 1989

    Google Scholar 

  19. Krempler F, Kostner GM, Roscher A, Haslauer F, Bolzano K, Sandhofer F: Studies on the role of specific cell surface receptors in the removal of lipoprotein (a) in man. J Clin Invest 71: 1431–1441, 1983

    Google Scholar 

  20. Kostner GM, Grillhofer HK: Lipoprotein (a) mediates high affinity low density lipoprotein association to receptor negative fibroblasts. J Biol Chem 266: 21287–21292, 1991

    Google Scholar 

  21. Bligh EG, Dyer WJ: Rapid method of total lipid extraction and purification. Can J Biochem Physiol 37: 911–917, 1959

    Google Scholar 

  22. El-Saadani M, Esterbauer H, El-Sayed M, Goher M, Nassar AY, Jürgens G: A spectrophotometric assay for lipid peroxides in serum lipoproteins using a commercially available reagent. J Lipid Res 30: 627–630, 1989

    Google Scholar 

  23. Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159, 1987

    Google Scholar 

  24. Maniatis T, Fritsch EF, Sambrook J: In: Molecular cloning: A laboratory manual, pp. 202–203. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1982

    Google Scholar 

  25. Bégin ME, Ells G, Horrobin DF: Polyunsaturated fatty acidinduced cytotoxicity against tumor cells and its relationship to lipid peroxidation. J Natl Cancer Inst 80: 188–194, 1988

    Google Scholar 

  26. Bégin ME, Ells G, Das UN, Horrobin DF: Differential killing of human carcinoma cells supplemented with n-3 and n-6 PUFAs. J Natl Cancer Inst 77: 1053–1062, 1986

    Google Scholar 

  27. Carroll KK: Experimental studies on dietary fat and cancer in relation to epidemiological data. Prog Clin Biol Res 222: 231–248, 1986

    Google Scholar 

  28. Carroll KK: Dietary fats and cancer. Am J Clin Nutr 53: 1064s-1067s, 1991

    Google Scholar 

  29. Morisaki N, Sprecher H, Milo GE, Cornwell DG: Fatty acid specificity in the inhibition of cell proliferation and its relationship to lipid peroxidation and prostaglandin biosynthesis. Lipids 17: 893–899, 1982

    Google Scholar 

  30. Ohkawa H, Ohishi N, Yagi K: Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95: 351–358, 1979

    Google Scholar 

  31. Asakawa T, Matsushita S: Thiobarbituric acid test for detecting lipid peroxides. Lipids 14: 401–406, 1980

    Google Scholar 

  32. Yagi K: A simple fluorometric assay for lipoperoxide in blood plasma. Biochem Med 15: 212–216, 1976

    Google Scholar 

  33. Esterbauer H, Cheeseman KH: Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydoxynonenal. Meth Enzymol 186: 407–421, 1990

    Google Scholar 

  34. Fujiwara F, Todo S, Imashuku S: Antitumor effect of gamma-linolenic acid on cultured human neuroblastoma cells. Prostaglandins Leukotrienes Med 23: 311–320, 1986

    Google Scholar 

  35. Grossman A, Wendel A: Non reactivity of the selenoenzyme glutathione peroxidase with enzymatically hydroperoxidized phospholipids. Eur J Biochem 135: 549–552, 1983

    Google Scholar 

  36. Thomas JP, Maiorino M, Ursini F, Girotti AW: Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation. J Biol Chem 265: 454–461, 1990

    Google Scholar 

  37. Maiorino M, Thomas JP, Girotti AW, Ursini F: Reactivity of phospholipid hydroperoxide glutathione peroxidase with membrane and lipoprotein lipid hydroperoxides. Free Rad Res Comms 12:13: 131–135, 1991

    Google Scholar 

  38. Sattler W, Maiorino M, Stocker R: Reduction of HDL- and LDL-associated cholesterylester and phospholipid hydroperoxides by phospholipid hydroperoxide glutathione peroxidase and Ebselen (PZ 51), in press

  39. Boscoboinik D, Szewczyk A, Hensey C, Azzi A: Inhibition of cell proliferation by alpha-tocopherol. Role of protein kinase C. J Biol Chem 266: 6188–6194, 1991

    Google Scholar 

  40. Boscoboinik D, Szewczyk A, Azzi A: Alpha-tocopherol (vitamin E) regulates vascular smooth muscle cell proliferation and protein kinase C activity. Arch Biochem Biophys 286: 264–269, 1991

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Medical Biochemistry, University of Graz, Harrachgasse 21, A-8010, Graz, Austria

    Véronique Chajès, Wolfgang Sattler, Alfred Stranzl & Gert M. Kostner

Authors
  1. Véronique Chajès
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wolfgang Sattler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alfred Stranzl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gert M. Kostner
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chajès, V., Sattler, W., Stranzl, A. et al. Influence of n-3 fatty acids on the growth of human breast cancer cellsin vitro: Relationship to peroxides and Vitamin-E. Breast Cancer Res Tr 34, 199–212 (1995). https://doi.org/10.1007/BF00689711

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00689711

Key words

Search

Navigation