Journal of Mammary Gland Biology and Neoplasia

, Volume 10, Issue 2, pp 189–196

Is Iodine A Gatekeeper of the Integrity of the Mammary Gland?

  • Carmen Aceves
  • Brenda Anguiano
  • Guadalupe Delgado
Article

Abstract

This paper reviews evidence showing iodine as an antioxidant and antiproliferative agent contributing to the integrity of normal mammary gland. Seaweed is an important dietary component in Asian communities and a rich source of iodine in several chemical forms. The high consumption of this element (25 times more than in Occident) has been associated with the low incidence of benign and cancer breast disease in Japanese women. In animal and human studies, molecular iodine (I2) supplementation exerts a suppressive effect on the development and size of both benign and cancer neoplasias. This effect is accompanied by a significant reduction in cellular lipoperoxidation. Iodine, in addition to its incorporation into thyroid hormones, is bound into antiproliferative iodolipids in the thyroid called iodolactones, which may also play a role in the proliferative control of mammary gland. We propose that an I2 supplement should be considered as an adjuvant in breast cancer therapy.

Keywords

mammary gland iodine deiodinase breast cancer antioxidant lipoperoxidation 

Abbreviations:

H2O2

hydrogen peroxide

I2

molecular iodine

I

iodide

I+

iodinium

I0

iodine free radical

I

oxidized iodine species

IO

hypoiodite

IO3

iodate

KI

potassium iodide

LPO

lactoperoxidase

MNU

N-methyl-N-nitrosourea

NIS

sodium iodide symporter

O2

single oxygen

O2

superoxide anions

OH

hydroxyl radicals

PEN

pendrin

PPAR

peroxisome proliferator-activated receptor

ROS

reactive oxygen species

T3

triiodothyronine

T4

thyroxine

TPO

thyroperoxidase

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References

  1. (1).
    Venturi S. Is there a role for iodine in breast disease? The Breast 2001;5:379–82.Google Scholar
  2. (2).
    Cann SA, van Netten JP, van Netten C. Hypothesis: Iodine, selenium and the development of breast cancer. Cancer Causes Control 2000;11:121–127.Google Scholar
  3. (3).
    Smyth PP. Role of iodine in antioxidant defence in thyroid and breast disease. Biofactors 2003;19:121–130.Google Scholar
  4. (4).
    Cocchi M, Venturi S. Iodide, antioxidant function and omega-6 and omega-3 fatty acids: A new hypothesis of biochemical cooperation? Prog Nutr 2000;2:15–9.Google Scholar
  5. (5).
    Thrall KD, Bull RJ. Differences in the distribution of iodine and iodide in the Sprague–Dawley rat. Fundam Appl Toxicol 1990;15:75–81.Google Scholar
  6. (6).
    Thrall KD, Sauer RL, Bull RJ. Evidence for thyroxine formation following iodine administration in Sprague–Dawley rats. J Toxicol Environ Health 1992;37:443–449.Google Scholar
  7. (7).
    Eskin BA, Grotkowski CE, Connolly CP, Ghent WR. Different tissue responses for iodine and iodide in rat thyroid and mammary glands. Biol Trace Elem Res 1995;49:9–18.Google Scholar
  8. (8).
    Ghent WR, Eskin BA, Low DA, Hill LP. Iodine replacement in fibrocystic disease of the breast. Can J Surg 1993;36:453–460.Google Scholar
  9. (9).
    Aceves C, Morales T, Pineda O, Rodón-Fonte C. Navarro L, Valverde-R C. T3 and iodine in milk. Mammary 5’deiodinase is neurally regulated. In: International symposium on hormones and bioactive substances in milk. Smolonice, Eslovak Republic; 1996; p 7.Google Scholar
  10. (10).
    Topper YJ, Freeman CS. Multiple hormone interaction in the developmental biology of the mammary gland. Physiol Rev 1980;60:1049–1067.Google Scholar
  11. (11).
    Memphan TB. Physiology of lactation. Philadelphia: Open University Press; 1987.Google Scholar
  12. (12).
    Tazebay UH, Wapnir IL, Levy O, Dohan O, Zuckier LS, Zhao QH, et al. The mammary gland iodide transporter is expressed during lactation and in breast cancer. Nature Med 2000;6:871–878.Google Scholar
  13. (13).
    Rillema JA, Williams CH, Moulden J, Golden KL. Effect of insulin on iodide uptake in mouse mammary gland explants. Exp Biol Med 2002;227:32–35.Google Scholar
  14. (14).
    Rillema JA, Hill MA. Prolactin regulation of the pendrin-iodide transporter in the mammary gland. Am J Physiol Endocrinol Metab 2003;284:E25–E28.Google Scholar
  15. (15).
    Kupper FC, Schweigert N, Ar Cali E, Legendre JM, Vilter H, Koareg B. Iodine uptake in laminariales involves extracellular, haloperoxidase-mediated oxidation of iodide. Planta 1998;207:163–171.Google Scholar
  16. (16).
    Hou X, Chai C, Quian Q, Yan X, Fan X. Determination of chemical species of iodine in some seaweeds (I). Sci Total Environ 1997;204:215–221.Google Scholar
  17. (17).
    Aceves C, Rodón C, Ramírez-C I, Wilson S, Pineda-C O, Lopez-B L, et al. Mammary 5′deiodinase (5′D) during the breeding cycle of the rat: Indirect evidence that 5′D type I is specific to the alveolar epithelium. Endocrine 1995;3:95–99.Google Scholar
  18. (18).
    García-Solís P, Alfaro Y, Anguiano B, Delgado G, Guzmán RC, Nandi S, Díaz-Muñoz M, Vázquez-Martínez O, Aceves C. Inhibition of induced-MNU mammary carcinogenesis by molecular iodine (I2) but not by iodide (I) treatment. Evidence that I2 prevents cancer promotion. Mol Cell Endocrinol, in press.Google Scholar
  19. (19).
    Strum JM. Site of iodination in rat mammary gland. Anat Rec 1978;192:235–244.Google Scholar
  20. (20).
    Wynne-Edwards KE. Breast cancer etiology and prevention from an evolutionary perspective. In: Review of lifestyle and environmental risk factors for breast cancer. The Canadian Breast Cancer Initiative (CBCI). Workshop on Primary Prevention of Breast Cancer. Vol. III, Québec City, Québec Canada; 2000. p. 1–31.Google Scholar
  21. (21).
    Helzlsouer KJ, Couzi R. Hormones and breast cancer. Cancer 1995;76:2059–2063.Google Scholar
  22. (22).
    Pihan GA, Doxsey SJ. The mitotic machinery as a source of genetic instability in cancer. Semin Cancer Biol 1999;9:289–302.Google Scholar
  23. (23).
    Shah NM, Eskin BA, Krouse TB, Sparks CE Iodoprotein formation by rat mammary glands during pregnancy and early postpartum period. Proc Soc Exp 1986;181:443–449.Google Scholar
  24. (24).
    Russo J, Russo IH, Role of differentiation in the pathogenesis and prevention of breast cancer. Endocr Rel Cancer 1997;4:7–21.Google Scholar
  25. (25).
    Haagensen CD. Disease of the breast. Philadelphia, PA: WB Saunders; 1971. p. 62.Google Scholar
  26. (26).
    Yoo KY, Tajima K, Kuroishi T, et al. Independent protective effect of lactation against breast cancer: A case-control study. Am J Epidemiol 1992;135:726–733.Google Scholar
  27. (27).
    Yang PS, Yang TL, Liu CL, Wu CW, Shen CY. A case control study of breast cancer in Taiwan. A low incidence area. Br J Cancer 1997;75:752–756.Google Scholar
  28. (28).
    Newcomb PA, Storer BE, Longnecker MP, et al. Lactation and reduced risk of premenopausal breast cancer. N Engl J Med 1994;330:81–87.Google Scholar
  29. (29).
    Michels KB,Willett WC, Rosner BA, et al. Prospective assessment of breastfeeding and breast cancer incidence among 89,887 women. Lancet 1996;347:431–436.Google Scholar
  30. (30).
    Ray G, Batra S, Shukla NK, Deo S, Raina V, Ashok S, Husain SA. Lipid peroxidation, free radical production and antioxidant status in breast cancer. Breast Cancer Res Treat 2000;59:163–170.Google Scholar
  31. (31).
    Cook JA, Gius D, Wink DA, Krishna MC, Russo A, Mitchell JB. Oxidative stress, redox, and the tumor microenvironment. Semin Radiat Oncol 2004;14:259–266.Google Scholar
  32. (32).
    Szatrowski TP, Nathan CF. Production or large amounts of hydrogen peroxide by human tumor cells. Cancer Res 1991;51:794–798.Google Scholar
  33. (33).
    Lane DP. p53 and human cancer. Br Med Bull 1994;50:582–599.Google Scholar
  34. (34).
    Bos J. The ras family and human carcinogenesis. Mutat Res 1988;195:255–271.Google Scholar
  35. (35).
    Moraes EC, Keyse SM, Tyrell RM. Mutagenesis by hydrogen peroxide treatment in mammalian cells: A molecular analysis. Carcinogenesis 1990;11:283–293.Google Scholar
  36. (36).
    Rilema JA, Hill MA. Pendrin transporter carries out iodide uptake into MCF-7 human mammary cancer Cells. Exp Biol Med 2003;228:1078–1081.Google Scholar
  37. (37).
    Zhang L, Sharma S, Zhu LX, Kogai T, Hershman JM, Brent GA, et al. Nonradioactive iodide effectively induces apoptosis in genetically modified lung cancer cells. Cancer Res 2003;63:5065–5072.Google Scholar
  38. (38).
    Schmutzler C, Brtko J, Biernert K, Köhrle J. Effects of retinoids and role of retinoic acid receptors in human thyroid carcinomas and cell lines derived therefrom. Exp Clin Endocrinol Diab 1996;10:393–406.Google Scholar
  39. (39).
    Schreck R, Schieders F, Schmutzler C, Köhrle J. Retinoids stimulate type I iodothyronine 5′-deiodinase activity in human follicular thyroid carcinoma cell lines. J Clin Endocrinol Metab 1994;79:791–798.Google Scholar
  40. (40).
    Aceves C, Gopainathrao G, Rajkumar L, Guzman RC, Yang J, Nandi S. Deiodinase type 1 (D1) in N-methyl-N-nitrosourea-induced rat mammary carcinomas. Differential expression in early and late arising tumors. 84th Annual Meeting. San Francisco CA: The Endocrine Society. 2002; pp. 731.Google Scholar
  41. (41).
    García-Solis P, Aceves C. 5′Deiodinase in two breast cancer cell lines: Effect of triiodothyronine, isoproterenol and retinoids. Mol Cell Endocrinol 2003;201:25–32.Google Scholar
  42. (42).
    Teas J, Harbison ML, Gelman RS. Dietary seaweed (Laminaria) and mammary carcinogenesis in rats. Cancer Res 1984;44:2758–2761.Google Scholar
  43. (43).
    Yamamoto I, Maruyama H, Moriguchi M. The effect of dietary seaweeds on 7,12-dimethyl-benz[a]anthracene-induced mammary tumorigenesis in rats. Cancer Lett. 1987;35:109–118.Google Scholar
  44. (44).
    Funahashi H, Imai T, Tanaka Y, Tsukamura K, Hayakawa Y, Kikumori T, et al. Wakame seaweed suppresses the proliferation of 7,12-dimethylbenz(a)-anthracene-induced mammary tumors in rats. Jpn J Cancer Res 1999;90:922–927.Google Scholar
  45. (45).
    Kato N, Funahashi H, Ando K, Takagi H. Suppressive effect of iodine preparations on proliferation of DMBA-induced breast cancer in rat. J Jpn Soc Cancer Ther 1994;29:582–588.Google Scholar
  46. (46).
    Funahashi H, Imai T, Tanaka Y, Tobinaga J, Wada M, Morita T, et al. Suppressive effect of iodine on DMBA-induced breast tumor growth in the rat. J Surg Oncol 1996;61:209–213.Google Scholar
  47. (47).
    Brown-Grant K, Rogers AW. The sites of iodide concentration in the oviduct and the uterous of the rat. J Endocrinol 1972;53:355–362.Google Scholar
  48. (48).
    Mutaku JF, Poma JF, Many MC, Denef JF, van Den Hove MF. Cell necrosis and apoptosis are differentially regulated during goiter development and iodine-induced involution. J Endocrinol 2002;172:375–386.Google Scholar
  49. (49).
    Pisarev M, Gärtner R. Autoregulatory actions of iodine. In: Braverman E, Utiger R, editors. Werner and Ingbar’s The Thyroid. A fundamental and clinical text. Philadelphia: Lippncott-Williams & Williams, 2000; p. 85–90.Google Scholar
  50. (50).
    Vitale M, Di Matola T, D’Ascoli F, Salzano S, Bogazzi F, Fenzi G, et al. Iodide excess induces apoptosis in thyroid cells through a p53-independent mechanism involving oxidative stress. Endocrinology 2000;141:598–605.Google Scholar
  51. (51).
    Boeynaems JM, Hubbard WC. Transformation of arachidonic acid into an iodolactone by the rat thyroid. J Biol Chem 1980;255:9001–9004.Google Scholar
  52. (52).
    Dugrillon A, Bechtner G, Uedelhoven WM, Weber PC, Gartner R. Evidence that an iodolactone mediates the inhibitory effect of iodide on thyroid cell proliferation but not on adenosine 3′-5′-monophosphate formation. Endocrinology 1990;127:337–343.Google Scholar
  53. (53).
    Langer R, Buzler C, Bechtner G, Gartner R. Influence of iodide and iodolactones on thyroid apoptosis. Exp Clin Endocrinol Diab 2003;111:325–329.Google Scholar
  54. (54).
    Arroyo-Helguera O, Aceves C. Mecanismos de captura y actividad antiproliferativa del yodo molecular (I2) en la línea celular de cáncer MCF-7. In: XXIV Congreso Nacional de la Sociedad Mexicana de Bioquímica, Zihuatanejo, Gro. México; 2004. pp. 345.Google Scholar
  55. (55).
    Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K, Evans RM. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 1994;91:7355–7359.Google Scholar
  56. (56).
    Shen Q, Brown PH. Novel agents for the prevention of breast cancer: Targeting transcription factors and signal transduction pathways. J Mammary Gland Biol Neoplasia 2003;8:45–73.Google Scholar
  57. (57).
    Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisley GB, Koble CS, Devchand P, Wahli W, Wilson TM, Lenhard JM, Lehmann JM. Fatty acids and eicosanoids regulate gene expression through direct interaction with peroxisome proliferator-activated receptors α and γ. Proc Nat Acad Sci USA 1997;94:4318–4323.Google Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Carmen Aceves
    • 1
    • 2
  • Brenda Anguiano
    • 1
  • Guadalupe Delgado
    • 1
  1. 1.Instituto de NeurobiologíaUniversidad Nacional Autónoma de MéxicoJuriquillaMéxico
  2. 2.Instituto de NeurobiologíaUniversidad Nacional Autónoma de MéxicoJuriquillaMéxico;

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