Fatty Acid Regulation of Breast Cancer Cell Growth and Invasion

  • David P. Rose
  • Jeanne M. Connolly
  • Xin-Hua Liu
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 422)


In 1993, the American Institute for Cancer Research organized its fourth Annual Symposium around the topic “Diet and Breast Cancer”. At that time, we discussed the influence of dietary fatty acids on human breast cancer cell growth, invasion and metastasis, and described the stimulatory effects of the polyunsaturated omega-6 fatty acids (n-6 FAs), and the inhibitory effects of the long-chain omega-3 fatty acids (n-3 FAs) on both cell proliferation and expression of the metastatic phenotype.1 Since then, progress has been made in understanding the distinct, but complementary, roles of cyclooxygenase and lipoxygenase products of n-6 FA metabolism in breast cancer progression. Also, further support has been obtained for a dietary intervention trial with n-3 FA supplementation, either alone or with selective pharmacological inhibitors of eicosanoid biosynthesis, in women at high breast cancer risk and/or as a novel approach to adjuvant therapy.


Breast Cancer Breast Cancer Cell Human Breast Cancer Cell Human Breast Cancer Cell Line Breast Cancer Cell Growth 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Rose, D.P., J.M. Connolly, and X.-H. Liu, Dietary fatty acids and human breast cancer cell growth, invasion, and metastasis, in: Diet and Breast Cancer, E.K. Weisburger, ed., Plenum Press, New York (1994).Google Scholar
  2. 2.
    Clark, G.M., C.R. Wenger, S. Beardslee, M.A. Owens, G. Pounds, T. Oldaker, P. Vendely, M.R. Pandian, D. Harrington, and W.L. McGuire, How to integrate steroid hormone receptor, flow cytometric, and other prognostic information in regard to primary breast cancer, Cancer 71: 2157–2162, (1993).CrossRefGoogle Scholar
  3. 3.
    Thompson, E.W., R. Reich, T.B. Shima, A. Albini, J. Graf, G.R. Martin, R.B. Dickson, and M.E. Lippman, Differential regulation of growth and invasiveness of MCF-7 breast cancer cells by antiestrogens. Cancer Res. 48: 6764–6768 (1988).Google Scholar
  4. 4.
    Ozzello, L. and M. Sordat, Behavior of tumors produced by transplantation of human mammary cell lines in athymic nude mice, Eur. J. Cancer 16: 553–559 (1980).Google Scholar
  5. 5.
    Price, J.M., and R.D. Zang. Studies of human breast cancer metastasis using nude mice, Cancer Metastasis Rev. 8:285–297 (1989/1990).Google Scholar
  6. 6.
    Thompson, E.W., N. Brunner, J. Torri, M.D. Johnson, V. Boulay. A. Wright, M.E. Lippman. P.S. Steeg, and R. Clarke, The invasive and metastatic properties of hormone-independent but hormone-responsive variants of MCF-7 human breast cancer cells, Clin. Exp. Metastasis 11: 15–26 (1993).CrossRefGoogle Scholar
  7. 7.
    Sommers, C.L., S.W. Byers, E.W. Thompson, J.A. Torri, and E.P. Gelmann, Differentiation state and invasiveness of human breast cancer cell lines, Breast Cancer Res. Treat. 31: 325–335 (1994).Google Scholar
  8. 8.
    Bandyopadhyay, G.K., W. Imagawa, D. Wallace, and S. Nandi, Linoleate metabolites enhance the in vitro proliferative response of mouse mammary epithelial cells to epidermal growth factor, J. Biol. Chem. 262: 2750–2756 (1987).Google Scholar
  9. 9.
    Bandyopadhyay, G.K., W. Imagawa, D. Wallace. and S. Nandi, Proliferative effects of insulin and epidermal growth factor on mouse mammary epithelial cells in primary culture. Enhancement by hydroxyeicosatetraenoic acids and synergism with prostaglandin E„ J. Biol. Chem. 263: 7567–7573 (1988).Google Scholar
  10. 10.
    Grammatikos, S.I., P.V. Subbaiah, T.A. Victor, and W.M. Miller, n-3 and n-6 fatty acid processing and growth effects in neoplastic and non-cancerous human mammary epithelial cell lines, Br. J. Cancer 70: 219–227 (1994).CrossRefGoogle Scholar
  11. 11.
    Wicha, M., L.A. Liotta, and W.R. Kidwell, Effects of unsaturated fatty acids on the growth of normal and neoplastic rat mammary epithelial cells, Cancer Res. 39: 426–435 (1978).Google Scholar
  12. 12.
    Rose, D.P., and J.M. Connolly, Effects of fatty acids and inhibitors of eicosanoid synthesis on the growth of a human breast cancer cell line in culture, Cancer Res. 50: 7139–7144 (1990).Google Scholar
  13. 13.
    Buckman, D.K., N.E. Hubbard, and K.L. Erickson, Eicosanoids and linoleate-enhanced growth of mouse mammary tumor cells, Prostaglandins Leukot. Essent. Fatty Acids 44: 117–184 (1991).CrossRefGoogle Scholar
  14. 14.
    Rose, D.P., Individual dietary fatty acids and the hormone-dependent cancers: animal studies, Am. J. Clin. Nutr. in press (1997).Google Scholar
  15. 15.
    Bardon, S., M.T. Le, and J.-M. Allesandri, Metabolic conversion and growth effects of n-6 and n-3 polyunsaturated fatty acids in the T47D breast cancer cell line, Cancer Lett. 99: 51–58 (1996).CrossRefGoogle Scholar
  16. 16.
    Rose, D.P., J.M. Connolly, and C.L. Meschter, Effect of dietary fat on human breast cancer growth and lung metastasis in nude mice, J. Natl. Cancer Inst. 83: 1491–1495 (1991).CrossRefGoogle Scholar
  17. 17.
    Meschter, C.L., J.M. Connolly, and D.P. Rose, Influence of regional location of the inoculation site, and dietary fat on the pathology of MDA-MB-435 human breast cancer cell-derived tumors grown in nude mice. Clin. Exp. Metastasis 10: 167–173 (1992).CrossRefGoogle Scholar
  18. 18.
    Rose, D.P., M.A. Hatala, J.M. Connolly, and J. Rayburn, Effect of diets containing different levels of linoleic acid on human breast cancer growth and lung metastasis in nude mice, Cancer Res. 53: 4686–4690 (1993).Google Scholar
  19. 19.
    Rose, D.P., J.M. Connolly, and X.-H. Liu, Effects of linoleic acid on the growth and metastasis of two human breast cancer cell lines in nude mice, and the invasive capacity of these cell lines in vitro, Cancer Res. 54: 6557–6562 (1994).Google Scholar
  20. 20.
    Gabor, H., L.A. Hillyard, and S. Abraham, Effect of dietary fat on growth kinetics of transplantable mammary adenocarcinoma in BALB/c mice, J. Natl. Cancer Inst. 74: 1299–1305 (1985).Google Scholar
  21. 21.
    Connolly, J.M., X.-H. Liu, and D.P. Rose, Dietary linoleic acid-stimulated human breast cancer cell growth and metastasis in nude mice and their suppression by indomethacin, a cyclooxygenase inhibitor, Nutr. Cancer 25: 231–240 (1996).Google Scholar
  22. 22.
    Kaizer, L., N.F. Boyd, V. Kriukov, and D. Trichler, Fish consumption and breast cancer risk: an ecological study, Nutr. Cancer 12: 61–68 (1989).Google Scholar
  23. 23.
    Kromann, N., and A. Green, Epidemiological studies in the Upernavik District, Greenland: incidence of some chronic diseases 1950–1974, Acta Med. Scand. 208: 401–406 (1980).Google Scholar
  24. 24.
    Parkinson, A.J., A.L. Cruz, W.L. Heyward, L.R. Bulkow, D. Hall, L. Barstaed, and W.E. Conner, Elevated concentrations of plasma co-3 polyunsaturated fatty acids among Alaskan Eskimos, Am. J. Clin. Nutr. 59: 384–388 (1994).Google Scholar
  25. 25.
    Lanier, A.P., L.R. Bulkow, and B. Ireland, Cancer in Alaskan Indians, Eskimos and Aleuts, 1969–83: Implications for etiology and control, Public Health Rep. 104: 658–665 (1989).Google Scholar
  26. 26.
    Caygill, C.P.J., A. Charlett, and M.J. Hill, Fat, fish, fish oil and cancer, Br. J. Cancer 74: 159–164 (1996).CrossRefGoogle Scholar
  27. 27.
    Kamano, K., H. Okuyama, R. Konishi, and H. Nagasawa, Effect of a high-linoleate and a high Ä-linolenate diet on spontaneous mammary tumorigenesis in mice, Anticancer Res. 9: 1903–1908 (1989).Google Scholar
  28. 28.
    Rose, D.P., J.M. Connolly, J. Rayburn, and M. Coleman, Influence of diets containing different levels of eicosapentaenoic or docosahexaenoic acid on the growth and metastasis of human breast cancer cells in nude mice, J. Natl. Cancer Inst. 87: 587–592 (1995).CrossRefGoogle Scholar
  29. 29.
    Rose, D.P., J.M. Connolly, and M. Coleman, Effect of omega-3 fatty acids on the progression of metastases after the surgical excision of human breast cancer cell solid tumors growing in nude mice, Clin. Cancer Res. in press.Google Scholar
  30. 30.
    Welsch, C.W., C.S. Oakley, C.-C. Chang, and M.A. Welsch, Suppression of growth by dietary fish oil of human breast carcinomas maintained in three different strains of immune-deficient mice, Nutr. Cancer 20: 119–127 (1993).Google Scholar
  31. 31.
    Rose, D.P. and J.M. Connolly, Effects of dietary omega-3 fatty acids on human breast cancer growth and metastasis in nude mice, J. Natl. Cancer Inst. 85: 1743–1747 (1993).CrossRefGoogle Scholar
  32. 32.
    Kannali, R.A., J. Marsh, and C. Fuchs, Effect of omega-3 fatty acids on growth of a rat mammary tumor, J. Natl. Cancer Inst. 73: 457–461 (1984).Google Scholar
  33. 33.
    Gabor, H., and S. Abraham, Effect of dietary menhaden oil on tumor cell loss and accumulation of mass of a transplantable adenocarcinoma in BALB/c mice, J. Natl. Cancer Inst. 76: 1223–1229 (1986).Google Scholar
  34. 34.
    DeWitt, D.L., Prostaglandin endoperoxide synthase: Regulation of enzyme expression, Biochim. Biophys. Acta, 1083: 121–134 (1991).CrossRefGoogle Scholar
  35. 35.
    Loll, P.J., and R.M. Garavito, The isoforms of cyclooxygenase: structure and function, Expert Opin. Invest. Drugs 3: 1171–1180 (1994).Google Scholar
  36. 36.
    Herschman, H.R., Regulation of prostaglandin synthase-1 and prostaglandin synthase-2, Cancer Metastasis Rev. 13: 241–256 (1994).CrossRefGoogle Scholar
  37. 37.
    Masferrer, J.L., B.S. Zweifel, P.T. Manning, S.D. Hauser, K.M. Leahy, W.G. Smith, P.C. lsakson, and K. Seibert, Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic, Proc. Natl. Acad. Sci. USA 91: 3228–3232 (1994).CrossRefGoogle Scholar
  38. 38.
    Müller-Decker, K., K. Scholz, F. Marks, and G. Fürstenberger, Differential expression of prostaglandin H synthase isozymes during multistage carcinogenesis in mouse epidermis, Mol. Carcinogenesis, 12: 31–41 (1995).CrossRefGoogle Scholar
  39. 39.
    Kargman, S.L., G.P. O’Neill, P.J. Vickers, J.F. Evans, J.A. Mancini, and S. Jothy, Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer, Cancer Res. 55: 2556–2559 (1995).Google Scholar
  40. 40.
    Spector, A.A., J.A. Gordon, and S.A. Moore, Hydroxyeicosatetraenoic acids (HETEs), Prog. Lipid Res. 27: 271–323 (1988).CrossRefGoogle Scholar
  41. 41.
    Yamamoto, S., Mammalian lipoxygenases: molecular and catalytic properties, Prostaglandins Leukot. Es-sent. Fatty Acids 35: 219–229 (1989)CrossRefGoogle Scholar
  42. 42.
    Chen, X.-S., U. Kurre, N.A. Jenkins, N.G. Copeland, and C.D. Funk, cDNA cloning, expression, mutagenesis of C-terminal isoleucine, genomic structure, and chromosomal localizations of murine 12-lipoxygenases, J. Biol. Chem. 269: 13979–13987 (1994).Google Scholar
  43. 43.
    Chang, W.-C., Y.-W. Liu, C.-C. Ning, H. Suzuki, T. Yoshimoto, and S. Yamamoto, Induction of arachidonate 12-lipoxygenase mRNA by epidermal growth factor in A431 cells, J. Biol. Chem. 268: 18734–18739 (1993).Google Scholar
  44. 44.
    Honn, K.V., D.G. Tang, X. Gao, I.A. Butovich, B. Liu, J. Timar, and W. Hagmann, 12-Lipoxygenases and 12(S)-HETE in cancer metastasis, Cancer Metastasis Rev. 13: 365–396 (1994).CrossRefGoogle Scholar
  45. 45.
    Krieg, P., A. Kinzig, M. Ress-Löschke, S. Vogel, B. Vanlandingham, M. Stephan, W.-D. Lehmann, F. Marks, and G. Furstenberger, 12-Lipoxygenase isoenzymes in mouse skin tumor development, Mol. Carcinogenesis, 14: 118–129 (1995).CrossRefGoogle Scholar
  46. 46.
    Corey, E.J., and J.E. Munroe, Irreversible inhibition of prostaglandin and leukotriene biosynthesis from arachidonic acid by I 1,12-dehydro- and 5,6-dehydroarachidonic acids, respectively, J. Am. Chem. Soc. 104: 1752–1754 (1982).CrossRefGoogle Scholar
  47. 47.
    Earashi, M., M. Noguchi, K. Kinoshita, 1. Miyazaki, M. Tanaka, and T. Sasaki, Effects of eicosanoid synthesis inhibitors on the in vitro growth and prostaglandin E and leukotriene B secretion of a human breast cancer cell line, Oncology 52: 150–155, 1995.Google Scholar
  48. 48.
    Noguchi, M., D.P. Rose, M. Earashi, and I. Miyazaki, The role of fatty acids and eicosanoid synthesis inhibitors in breast carcinoma, Oncology, 52: 265–271 (1995).CrossRefGoogle Scholar
  49. 49.
    Connolly, J.M., and D.P. Rose, Effects of fatty acids on invasion through reconstituted basement membrane (“Matrigel”) by a human breast cancer cell line, Cancer Lett. 75: 137–142 (1993).CrossRefGoogle Scholar
  50. 50.
    Liu, X.-H., and D.P. Rose, Stimulation of type IV collagenase expression by linoleic acid in a metastatic human breast cancer cell line. Cancer Lett. 76: 71–77 (1994).CrossRefGoogle Scholar
  51. 51.
    Liu, X.-H., and D.P. Rose, Suppression of type IV collagenase in MDA-MB-435 human breast cancer cells by eicosapentaenoic acid in vitro and in vivo, Cancer Lett. 92: 21–26 (1995).CrossRefGoogle Scholar
  52. 52.
    Liu, X.-H., J.M. Connolly, and D.P. Rose, Eicosanoids as mediators of linoleic acid-stimulated invasion and type IV collagenase production by a metastatic human breast cancer cell line, Clin. Exp. Metastasis 14: 145–152 (1996).CrossRefGoogle Scholar
  53. 53.
    Hubbard, N.E., and K.L. Erickson, Enhancement of metastasis from a transplantable mouse mammary tumor by dietary linoleic acid, Cancer Res. 47: 6171–6175 (1987).Google Scholar
  54. 54.
    Rolland, P.H., P.M. Martin, J. Jacquemier, A.M. Rolland, and M. Toga, Prostaglandin in human breast cancer: evidence suggesting that an elevated prostaglandin production is a marker of high metastatic potential for neoplastic cells, J. Natl. Cancer Inst. 64: 1061–1070 (1980).Google Scholar
  55. 55.
    Fulton, A.M., and G.H. Heppner, Relationships of prostaglandin E and natural killer sensitivity to metastatic potential in murine mammary adenocarcinomas. Cancer Res. 45: 4779–4784 (1985).Google Scholar
  56. 56.
    Vignon, F., F. Capony, M. Chambon, G. Freiss, M. Garcia, and H. Rochefort, Autocrine growth stimulation of the MCF-7 breast cancer cells by the estrogen-regulated 52K protein, Endocrinology 118: 1537–1545 (1986).CrossRefGoogle Scholar
  57. 57.
    Vetvick, V., J. Vektvickovâ. and M. Fusek, Effect of procathepsin D on proliferation of human cell lines, Cancer Lett. 79: 131–135 (1994).Google Scholar
  58. 58.
    Kirchheimer, J.C., J. Wojita, G. Christ, and B.R. Binder, Proliferation ofa human epidermal tumor cell line stimulated by urokinase, EASES J. 1: 125–128 (1987)Google Scholar
  59. 59.
    Kirchheimer, J.C., J. Wojita, G. Christ, and B.R. Binder, Functional inhibition of endogenously produced urokinase decreases cell proliferation in a human melanoma cell line, Proc. Natl. Acad. Sci. USA 86: 5424–5428 (1989)CrossRefGoogle Scholar
  60. 60.
    Patthy, L, Evolution of the proteases of blood coagulation and fibrinolysis by assembly of molecules. Cell 41: 657–663 (1985).CrossRefGoogle Scholar
  61. 61.
    Suto, Y., and D.B. Rifkin, Inhibition of endothelial cell movement by pericytes and smooth muscle cells. Activation of a latent transforming growth factor-beta- I-like molecule by plasmin during co-culture, J. Cell Biol. 109: 309–315 (1989).CrossRefGoogle Scholar
  62. 62.
    Long, B.J., and D.P. Rose, Modulation of plasminogen activator (PA) activity by linoleic acid in two metastatic human breast cancer cell lines, Proc. Am. Assoc. Cancer Res. 36: 75 (1995).Google Scholar
  63. 63.
    Clarke, R., E.W. Thompson, F. Leonessa, J. Lippman, M. McGarvey, T.L. Frandsen, and N. Brunner, Hormone resistance, invasiveness, and metastatic potential in breast cancer, Breast Cancer Res. Treat. 24: 227–239 (1993).Google Scholar
  64. 64.
    Liu, X.-H., J.M. Connolly, and D.P. Rose. The 12-lipoxygenase gene-transfected MCF-7 human breast cancer cell line exhibits estrogen-independent, but estrogen and omega-6 fatty acid-stimulated proliferation in vitro,and enhanced growth in athymic nude mice, Cancer Lett. - in press.Google Scholar
  65. 65.
    Low, J.A., M.D. Johnson, E.A. Bone, and R.B. Dickson, The matrix metalloproteinase inhibitor batimastat (BB-94) retards human breast cancer solid tumor growth but not ascites formation in nude mice, Clin. Cancer Res. 2: 1207–1214 (1996).Google Scholar
  66. 66.
    Baillie, C.T., M.C. Winslet, and N.J. Bradley, Tumour vasculature-a potential therapeutic target, Br. J. Cancer 72: 257–267 (1995).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • David P. Rose
    • 1
  • Jeanne M. Connolly
    • 1
  • Xin-Hua Liu
    • 1
  1. 1.Division of Nutrition and EndocrinologyAmerican Health FoundationValhallaUSA

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