Hostname: page-component-586b7cd67f-tf8b9 Total loading time: 0 Render date: 2024-11-23T12:30:50.990Z Has data issue: false hasContentIssue false
  • English
  • Français

n-3 Fatty acids and lipid peroxidation in breast cancer inhibition

Published online by Cambridge University Press:  09 March 2007

Basil A. Stoll
Basil A. Stoll*
Affiliation:
Oncology Department, St Thomas' Hospital, London SE1 7EH, UK
*
Corresponding author: Dr Basil A. Stoll, fax +44 20 7928 9968.
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Long-chain n-3 fatty acids (FA) consistently inhibit the growth of human breast cancer (BC) cells both in culture and in grafts in immunosuppressed mice. Large cohort studies have, however, failed to confirm a protective effect for fish oils rich in n-3 FA against BC risk. The present review examines new evidence on biological mechanisms which may be involved in the inhibition of mammary carcinogenesis by long-chain n-3 FA, focusing on an apoptotic effect by its lipid peroxidation products. Dietary intake of n-3 FA leads to their incorporation into cell membrane lipids. Increased apoptosis in human BC cells following exposure to long-chain n-3 FA such as eicosapentaenoic and docosahexaenoic acids is generally ascribed to their inhibition of cyclooxygenase 2 which promotes mammary carcinogenesis. In addition however, long-chain n-3 FA are particularly likely to activate peroxisome proliferator-activated receptor (PPAR)-γ, a key regulator of lipid metabolism but also capable of modulating proliferative activity in a variety of cells including mammary cells. Expression of PPAR-γ in the nucleus is activated by second messengers such as J series prostaglandins and the latter have been shown to cause apoptosis in vivo in explants of human BC cells in immunosuppressed mice. In mammary tumours, it is observed that long-chain FA not only increase apoptosis, but also increase lipid peroxidation, and the apoptotic effect can be reversed by antioxidants. The rationale for use of n-3 FA dietary supplements in counteracting BC progression needs to be tested clinically in a phase 2 pilot study, while at the same time, the effect on whole-body lipid peroxidation needs to be monitored. Dietary supplements of fish oil rich in n-3 FA are proposed for premenopausal women over the age of 40 years who are shown to be at increased BC risk. Biological markers in breast tissue of BC progression will be monitored, and observed changes related to serial plasma levels of isoprostanes as a measure of whole-body lipid peroxidation.

Keywords

AntioxidantsApoptosisBreast cancerDietary interventionn-3 Fatty acids
Type
Review article
Information
British Journal of Nutrition , Volume 87 , Issue 3 , March 2002 , pp. 193 - 198
Copyright
Copyright © The Nutrition Society 2002

References

Anti, M, Armelao, F, Marra, G, Percesepe, A, Bartoli, GM, Palozza, P & Parrella, P (1994) Effects of different doses of fish oil on rectal cell proliferation in patients with sporadic colonic adenomas. Gastroenterology 107, 1709–1718.CrossRefGoogle ScholarPubMed
Badawi, A, El-Sohemy, A, Stephen, LL, Ghoshai, AK & Archer, MC (1998) The effect of dietary n-3 and n-6 polyunsaturated fatty acids on the expression of cyclooxygenase 1 and 2 and levels of p21ras in rat mammary glands. Carcinogenesis 19, 903–910.CrossRefGoogle ScholarPubMed
Bagga, D, Capone, S, Wang, HJ, Heber, D, Lill, M, Chap, L & Glaspy, JA (1997) Dietary modulation of n-3/n-6 polyunsaturated fatty acid ratios in patients with breast cancer. Journal of the National Cancer Institute 89, 1123–1131.CrossRefGoogle Scholar
Bandyopadhyay, GK, Hwang, S, Imagawa, W & Nandi, S (1993) Role of PUFA as signal transducers; amplification of signals from growth factor receptors by fatty acids in mammary epithelial cells. Prostaglandins, Leukotrienes and Essential Fatty Acids 48, 71–78.CrossRefGoogle Scholar
Bartoli, GM, Palazza, P, Marra, G, Armelao, F, Francescelli, P & Luberto, C (1993) n-3 PUFA and alpha-tocopherol control of tumour cell proliferation. Molecular Aspects of Medicine 14, 247–252.CrossRefGoogle Scholar
Bartsch, H, Nair, J & Owen, AW (1999) Dietary polyunsaturated fatty acids and cancers of the breast and colorectum; emerging evidence for their role as risk modifiers. Carcinogenesis 20, 2209–2218.CrossRefGoogle ScholarPubMed
Betteridge, DJ (2000) What is oxidative stress? Metabolism 49 Suppl. 1, 3–8.CrossRefGoogle ScholarPubMed
Birt, DF (1990) The influence of dietary fat on carcinogenesis; lessons from experimental models. Nutrition Reviews 48, 1–5.CrossRefGoogle ScholarPubMed
Bougnoux, P, Germain, E, Chajes, V, Hubert, B, Lhuillery, C, Le Floch, O, Body, G & Calais, G (1999) Cytotoxic drugs efficacy correlates with adipose tissue DHA level in locally advanced breast carcinoma. British Journal of Cancer 79, 1765–1769.CrossRefGoogle Scholar
Bougnoux, P, Koscielny, S, Chajes, V, Descamps, P, Couet, C & Calais, G (1994) Alpha-linolenic acid content of adipose tissue; a host determinant of the risk of early metastasis in breast cancer patients. British Journal of Cancer 70, 330–334.CrossRefGoogle Scholar
Brueggemeier, AW, Quinn, AL, Parrett, ML, Joarder, FS, Harris, RE & Robertson, FM (1999) Correlation of aromatase and cyclooxygenase gene expression in human breast cancer specimens. Cancer Letters 140, 27–35.CrossRefGoogle ScholarPubMed
Caygill, CPJ, Charlett, A & Hill, MJ (1996) Fat, fish oil and cancer. British Journal of Cancer 74, 159–164.Google Scholar
Chajes, V, Lhuillery, C, Sattler, W, Kostner, GM & Bougnoux, P (1996) Alpha-tocopherol and hydroperoxide content in breast adipose tissue from patients with breast tumors. International Journal of Cancer 67, 170–175.3.0.CO;2-Q>CrossRefGoogle ScholarPubMed
Chajes, V, Sattler, W, Stranzl, A & Kestner, GM (1995) Influence of n-3 fatty acids on the growth of human breast cancer cells in vitro; relationship to peroxides and vitamin E. Breast Cancer Research and Treatment 34, 199–212.CrossRefGoogle ScholarPubMed
Clay, CE, Namen, AM, Atsumi, G, Willingham, MC, High, KP, Kute, TE & Trimboli, AJ (1999) Influence of J series prostaglandins in apoptosis and tumorigenesis of breast cancer cells. Carcinogenesis 20, 1905–1911.CrossRefGoogle ScholarPubMed
Cognault, S, Jourdan, ML, Germain, E, Pitavy, R, Morei, E, Duraha, G & Bougnoux, R (2000) Effect of alpha-linolenic acid-rich diet on mammary tumor growth depends on the dietary oxidative status. Nutrition in Cancer 36, 33–41.CrossRefGoogle ScholarPubMed
Cohen, LA, Thompson, DO, Choi, K, Karmali, RA & Rose, DP (1986) Dietary fat and mammary cancer; modulation of serum and tumor lipid composition and tumor prostaglandins by different dietary fats. National Journal of Cancer Institute 77, 43–51.Google ScholarPubMed
Das, UN (1999) Essential fatty acids, lipid peroxidation and apoptosis. Prostaglandins, Leukotrienes and Essential Fatty Acids 61, 157–163.Google Scholar
Elstner, E, Muller, C, Keshizuka, K, Williamson, EA, Park, D, Asou, H & Shintaku, P (1998) Ligands for PPAR gamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells. Proceedings of the National Academy of Science, USA 95, 8806–8811.Google Scholar
Germain, E, Chajes, V, Cognault, S, Lhuillery, C & Bougnoux, P (1998) Enhancement of doxorubicin cytotoxicity by polyunsaturated fatty acids in the human breast tumor cell line MDA-MB-231; relationship to lipid peroxidation. International Journal of Cancer 75, 578–583.3.0.CO;2-5>CrossRefGoogle ScholarPubMed
GISSI-Prevenzione Investigators (1999) Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction; results of the GISSI-Prevenzione trial. Lancet 354, 447–455.CrossRefGoogle Scholar
Gonzalez, MJ, Schemmel, RA, Dugan, L Jr, Gray, JI & Welsch, CW (1993) Dietary fish oil inhibits human breast carcinoma growth; a function of increased lipid peroxidation. Lipids 28, 827–832.CrossRefGoogle ScholarPubMed
Gopaul, NK, Halliwell, B & Anggard, EE (2000) Measurement of plasma F2-isoprostanes as an index of lipid peroxidations does not appear to be confounded by diet. Free Radical Research 33, 115–127.CrossRefGoogle Scholar
Gordge, PC, Hulme, MJ, Clegg, RA & Miller, WR (1996) Elevation of protein kinase C activities in malignant as compared with normal human breast tissue. European Journal of Cancer 32, 2120–2126.CrossRefGoogle Scholar
Groop, LC, Bonadonna, RC, Simonsen, DC, Petrides, AS, Shank, M & De Fronzo, RA (1992) Effect of insulin on oxidative and nonoxidative pathways of free fatty acid metabolism in human obesity. American Journal of Physiology 263, E79–E84.Google ScholarPubMed
Halliwell, B (1999) Establishing the significance and optimal intake of dietary antioxidants; the biomarker concept. Nutrition Reviews 57, 104–113.CrossRefGoogle ScholarPubMed
Holmes, MD, Hunter, DJ & Colditz, GA (1999) Association of dietary intake of fat and fatty acids with risk of breast cancer. Journal of the American Medical Association 281, 915–920.Google Scholar
Huang, YC, Jessup, JM, Forse, RA, Flickner, S, Pleskow, D & Anastopoulos, HT (1996) n-3 Fatty acids decrease colonic epithelial cell proliferation in high risk bowel mucosa. Lipids 31, Suppl., 313–317.CrossRefGoogle ScholarPubMed
Hursting, SD, Thornqvist, M & Henderson, MM (1990) Types of dietary fat and the incidence of cancer at five sites. Preventive Medicine 19, 242–253.CrossRefGoogle ScholarPubMed
Jump, DB, Clarke, SD, Thelen, A, Liimatta, M, Ren, B & Badin, MV (1997) Dietary fat, genes and human health. Experimental Medical Biology 422, 167–176.CrossRefGoogle ScholarPubMed
Kaizer, L, Boyd, NF, Kriukov, V & Tritchler, D (1989) Fish consumption and breast cancer risk; ecological study. Nutrition in Cancer 12, 61–68.CrossRefGoogle ScholarPubMed
Karmali, RS, Marsh, J & Fuchs, C (1984) Effects of omega-3 fatty acids on growth of rat mammary tumors. Journal of the National Cancer Institute 73, 457–461.CrossRefGoogle Scholar
Kimmick, GG, Bell, R & Bostick, RM (1997) Vitamin E and breast cancer; a review. Nutrition in Cancer 27, 109–117.CrossRefGoogle ScholarPubMed
Klein, V, Chajes, V, Germain, E, Schulgen, G, Pinault, M, Malvy, D & Lefrancq, T (2000) Low alpha-linolenic acid content of adipose breast tissue is associated with an increased risk of breast cancer. European Journal of Cancer 36, 335–360.CrossRefGoogle ScholarPubMed
Mantzioris, E, Cleland, LG, Gibson, RA, Neumann, MA, Demassi, M & James, MJ (2000) Biochemical effects of a diet containing foods enriched with n-3 fatty acids. American Journal of Clinical Nutrition 72, 42–48.Google Scholar
Martinez, M, Vazquez, E, Garcia-Silva, MT, Manzanares, J, Bertran, JM, Castello, F & Mougan, I (2000) Therapeutic effects of DHA ethyl ester in patients with peroxisomal disorders. American Journal of Clinical Nutrition 72 Suppl., 376–385.CrossRefGoogle Scholar
Meade, EA, McIntyre, TM, Zimmerman, GA & Prescott, SM (1999) Peroxisome proliferators enhance cyclooxygenase-2 expression in epithelial cells. Journal of Biological Chemistry 274, 8328–8334.CrossRefGoogle ScholarPubMed
Mueller, E, Sarraf, P, Tontonoz, P, Evans, RM, Martin, KJ, Zhang, M & Fletcher, C (1998) Terminal differentiation of human breast cancer through PPAR gamma. Molecular Cell 1, 465–470.CrossRefGoogle ScholarPubMed
Noguchi, M, Mimami, M, Yagasaki, R, Kinoshita, K, Earashi, M & Katagawa, H (1997) Chemoprevention of IMBA-induced mammary carcinogenesis in rats by low dose EPA and DHA. British Journal of Cancer 75, 348–353.CrossRefGoogle ScholarPubMed
Noguchi, M, Rose, DP, Earashi, M & Miyazaki, I (1995) The role of fatty acids and eicosanoid-synthesis inhibitors in breast carcinoma. Oncology 52, 265–271.CrossRefGoogle ScholarPubMed
Paolisso, G & Giugliano, D (1996) Oxidative stress and insulin action; is there a relationship? Diabetologia 39, 357–363.CrossRefGoogle ScholarPubMed
Platet, N, Prevostel, C, Derocq, D, Joubert, D, Rochefort, H & Garcia, M (1998) Breast cancer cell invasiveness; correlation with PKC activity and differential regulation by phorbol ester in ER positive and negative cells. International Journal of Cancer 75, 750–756.3.0.CO;2-A>CrossRefGoogle ScholarPubMed
Prietto, J, Filippis, A, Nakhla, C & Clarke, S (1999) Nutrient induced insulin resistance. Molecular and Cellular Endocrinology 151, 143–149.CrossRefGoogle Scholar
Roberts, JL, Montine, TJ, Markesbury, WR, Tapper, AR, Hardy, P, Chemtab, S & Dettbaru, WD (1998) Formation of isoprostase-like compounds in vivo from docosahexaenoic acid. Journal of Biological Chemistry 273, 13605–13612.Google Scholar
Rose, DP & Connolly, JM (1993) Effects of dietary n-3 fatty acids on human breast cancer growth and metastasis in nude mice. Journal of the National Cancer Institute 85, 1743–1746.Google Scholar
Rose, DP, Connolly, JM & Coleman, M (1996) Effect of n-3 fatty acids on the progression of metastases after excision of human breast cancer cell solid tumors growing in nude mice. Clinical Cancer Research 2, 1751–1756.Google Scholar
Rose, DP, Hatala, MA, Connolly, JM & Rayburn, J (1993) Effects of diet containing different levels of linoleic acid on human breast cancer growth and lung metastasis in nude mice. Cancer Research 53, 4686–4689.Google Scholar
Sessler, AM & Ntambi, JM (1998) Polyunsaturated fatty acid regulation of gene expression. Journal of Nutrition 128, 923–926.CrossRefGoogle ScholarPubMed
Simonsen, N, van't Veer, P, Strain, JJ, Martin-Moreno, JM, Hlttunen, JK & Navajas, JF (1998) Adipose tissue n-3 and n-6 fatty acid content, and breast cancer in the EURAMIC study. American Journal of Epidemiology 147, 342–352.CrossRefGoogle Scholar
Singh, I, Moser, AB, Goldfischer, S & Moser, HW (1984) Lignoceric acid is oxidised in the peroxisome: Implications for the Zellweger syndrome and adrenoleukodystrophy. Proceedings of the National Academy of Science, USA 81, 4203–4207.CrossRefGoogle ScholarPubMed
Song, JH, Fujimoto, K & Miyazawa, T (2000) Polyunsaturated fatty acids (n-3) susceptible to peroxidation are increased in plasma and tissue lipids of rats fed DHA-containing oils. Journal of Nutrition 130, 3028–3033.CrossRefGoogle Scholar
Steinberg, D & Lewis, A (1997) Oxidative modification of LDL and atherogenesis. Circulation 95, 1062–1071.CrossRefGoogle ScholarPubMed
Stoll, BA (1999) Perimenopausal weight gain and progression of breast cancer precursors. Cancer Detection and Prevention 23, 31–36.Google Scholar
Stoll, BA (2002) Oestrogen/IGF-1 receptor interaction in early breast cancer. Clinical implications. Annals of Oncology (In the press).Google Scholar
Toniolo, P, Riboli, E, Shore, RE & Pasternack, BS (1994) Consumption of meat, animal protein and fat and risk of breast cancer; a prospective cohort study in New York. Epidemiology 5, 391–397.Google Scholar
Traber, MG & Packer, L (1995) Vitamin E; beyond antioxidant function. American Journal of Clinical Nutrition 62, Suppl. 6, 1501–1509.CrossRefGoogle ScholarPubMed
Vatten, LJ, Solvell, K & Loken, EB (1990) Frequency of meat and fish intake and risk of breast cancer in a prospective study of 14,500 Norwegian women. International Journal of Cancer 46, 12–15.CrossRefGoogle Scholar
Weisburger, JH (2000) Approaches for chronic disease prevention based on current understanding of underlying mechanisms. American Journal of Clinical Nutrition 71 Suppl., 1710–1714.Google Scholar
Welsch, CW (1987) Enhancement of mammary tumorigenesis by dietary fat; review of potential mechanisms. American Journal of Clinical Nutrition 45, 192–202.Google Scholar
Welsch, CW (1995) Review of the effects of dietary fat on experimental mammary gland tumorigenesis; role of lipid peroxidation. Free Radical in Biology and Medicine 18, 757–773.Google Scholar
Wynder, EL, Cohen, LA, Muscat, JE, Winters, B, Dwyer, JT & Blackburn, G (1997) Breast cancer; weighing the evidence of a promoting role of dietary fat. Journal of the National Cancer Institute 11, 766–775.Google Scholar
Yam, D, Eliraz, A & Berry, EM (1996) Diet and disease, the Israeli paradox. Possible dangers of a high omega-6 fat diet. Israeli Journal of Medical Science 32, 1134–1143.Google Scholar
Zhu, ZR, Parviainen, M, Mannisto, S, Pietinen, P, Eskelinen, M & Syrjanen, K (1996) Vitamin E concentration in breast adipose tissue of breast cancer patients. Cancer Causes and Control 7, 591–595.CrossRefGoogle ScholarPubMed