Biological Trace Element Research

, Volume 184, Issue 1, pp 186–195 | Cite as

Dietary Supplementation with Methylseleninic Acid Inhibits Mammary Tumorigenesis and Metastasis in Male MMTV-PyMT Mice

  • Sneha Sundaram
  • Lin Yan


Male breast cancer, which makes up approximately 1% of all breast cancers, is an aggressive disease with poor prognosis. We investigated the effects of dietary supplementation with selenium in the form of methylseleninic acid [(MSeA) 2.5 mg selenium/kg] on mammary tumorigenesis in male MMTV-PyMT mice. The mammary tumor latency was 14.6 weeks for the MSeA-fed group and 13.8 weeks for the controls fed the AIN93G diet (p < 0.05). Dietary supplementation with MSeA, versus the control, resulted in a 72% reduction in tumor progression, a 46% reduction in both final volume and weight of mammary tumors, and a 70% reduction in the number of lung metastases. Mammary tumorigenesis in MMTV-PyMT mice, versus non-tumor-bearing wild-type mice, resulted in significant increases in concentrations of plasminogen activator inhibitor-1, urokinase plasminogen activator, monocyte chemotactic protein-1, and vascular endothelial growth factor, but not aromatase and estrogen, in the plasma. Concentrations of all variables mentioned above in both plasma and mammary tumors were lower in MSeA-fed mice. Mammary tumorigenesis reduced plasma levels of adiponectin compared to non-tumor-bearing controls. Adiponectin concentrations in mammary tumors, but not in plasma, were higher in MSeA-fed mice than in controls. In summary, dietary supplementation with selenium in the form of MSeA inhibits mammary tumorigenesis and its pulmonary metastasis in male MMTV-PyMT mice.


MMTV-PyMT Selenium Mammary tumorigenesis Metastasis Male 



The authors acknowledge the assistance of the following staff: Lana DeMars, Kay Keehr, and Nicole Hollar for technical support, Craig Lacher for selenium analysis, LuAnn Johnson for statistical analysis, James Lindlauf for making animal diets, and the vivarium staff for providing high-quality animal care. Funding for this work was provided by the U.S. Department of Agriculture, Agriculture Research Service, Research Project 5450-51000-045-00D.


  1. 1.
    White J, Kearins O, Dodwell D, Horgan K, Hanby AM, Speirs V (2011) Male breast carcinoma: increased awareness needed. Breast Cancer Res 13(5):219. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Stalsberg H, Thomas DB, Rosenblatt KA, Jimenez LM, McTiernan A, Stemhagen A, Thompson WD, Curnen MG, Satariano W, Austin DF et al (1993) Histologic types and hormone receptors in breast cancer in men: a population-based study in 282 United States men. Cancer Causes Control 4(2):143–151. CrossRefPubMedGoogle Scholar
  3. 3.
    Foerster R, Schroeder L, Foerster F, Wulff V, Schubotz B, Baaske D, Rudlowski C (2014) Metastatic male breast cancer: a retrospective cohort analysis. Breast Care (Basel) 9(4):267–271. CrossRefGoogle Scholar
  4. 4.
    Kornegoor R, Verschuur-Maes AH, Buerger H, Hogenes MC, de Bruin PC, Oudejans JJ, van der Groep P, Hinrichs B, van Diest PJ (2012) Molecular subtyping of male breast cancer by immunohistochemistry. Mod Pathol 25(3):398–404. CrossRefPubMedGoogle Scholar
  5. 5.
    Parise CA, Caggiano V (2014) Breast cancer survival defined by the ER/PR/HER2 subtypes and a surrogate classification according to tumor grade and immunohistochemical biomarkers. J Cancer Epidemiol 2014:469251. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S, Backlund MG, Yin Y, Khramtsov AI, Bastein R, Quackenbush J, Glazer RI, Brown PH, Green JE, Kopelovich L, Furth PA, Palazzo JP, Olopade OI, Bernard PS, Churchill GA, Van Dyke T, Perou CM (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8(5):R76. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Guy CT, Cardiff RD, Muller WJ (1992) Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol 12(3):954–961. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Giordano SH, Buzdar AU, Hortobagyi GN (2002) Breast cancer in men. Ann Intern Med 137(8):678–687. CrossRefPubMedGoogle Scholar
  9. 9.
    Lockwood K, Moesgaard S, Hanioka T, Folkers K (1994) Apparent partial remission of breast cancer in ‘high risk’ patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10. Mol Asp Med 15(Suppl):S231–S240.CrossRefGoogle Scholar
  10. 10.
    Meyer F, Galan P, Douville P, Bairati I, Kegle P, Bertrais S, Estaquio C, Hercberg S (2005) Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trial. Int J Cancer 116(2):182–186. CrossRefPubMedGoogle Scholar
  11. 11.
    Qiao YL, Dawsey SM, Kamangar F, Fan JH, Abnet CC, Sun XD, Johnson LL, Gail MH, Dong ZW, Yu B, Mark SD, Taylor PR (2009) Total and cancer mortality after supplementation with vitamins and minerals: follow-up of the Linxian General Population Nutrition Intervention Trial. J Natl Cancer Inst 101(7):507–518. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Yu SY, Zhu YJ, Li WG (1997) Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol Trace Elem Res 56(1):117–124. CrossRefPubMedGoogle Scholar
  13. 13.
    Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, Parnes HL, Minasian LM, Gaziano JM, Hartline JA, Parsons JK, Bearden JD 3rd, Crawford ED, Goodman GE, Claudio J, Winquist E, Cook ED, Karp DD, Walther P, Lieber MM, Kristal AR, Darke AK, Arnold KB, Ganz PA, Santella RM, Albanes D, Taylor PR, Probstfield JL, Jagpal TJ, Crowley JJ, Meyskens FL Jr, Baker LH, Coltman CA Jr (2009) Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301(1):39–51. CrossRefPubMedGoogle Scholar
  14. 14.
    Combs GF, Yan L (2016) Status of selenium in cancer prevention. In: Hatfield DL, Berry MJ, Gladyshev VN (eds) Selenium—its molecular biology and role in human health. Springer-Verlag, New York, pp 321–332. Google Scholar
  15. 15.
    Jackson MI, Combs GF Jr (2008) Selenium and anticarcinogenesis: underlying mechanisms. Curr Opin Clin Nutr Metab Care 11(6):718–726. CrossRefPubMedGoogle Scholar
  16. 16.
    Ip C, Thompson HJ, Zhu Z, Ganther HE (2000) In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention. Cancer Res 60(11):2882–2886.PubMedGoogle Scholar
  17. 17.
    Schrauzer GN (2006) Interactive effects of selenium and chromium on mammary tumor development and growth in MMTV-infected female mice and their relevance to human cancer. Biol Trace Element Res 109(3):281–292. CrossRefGoogle Scholar
  18. 18.
    Qi Y, Fu X, Xiong Z, Zhang H, Hill SM, Rowan BG, Dong Y (2012) Methylseleninic acid enhances paclitaxel efficacy for the treatment of triple-negative breast cancer. PLoS One 7(2):e31539. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Yazdi MH, Mahdavi M, Setayesh N, Esfandyar M, Shahverdi AR (2013) Selenium nanoparticle-enriched Lactobacillus brevis causes more efficient immune responses in vivo and reduces the liver metastasis in metastatic form of mouse breast cancer. DARU J Pharmaceutical Sci 21(1):33. CrossRefGoogle Scholar
  20. 20.
    Sundaram S, Yan L (2016) High-fat diet enhances mammary tumorigenesis and pulmonary metastasis and alters inflammatory and angiogenic profiles in MMTV-PyMT mice. Anticancer Res 36(12):6279–6287. CrossRefPubMedGoogle Scholar
  21. 21.
    Reeves PG, Nielsen FH, Fahey GCJ (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123(11):1939–1951.CrossRefPubMedGoogle Scholar
  22. 22.
    Institute for Laboratory Animal Research (2011) Guide for the care and use of laboratory animals, 8th edn. National Academies Press, Washington, D.C. Google Scholar
  23. 23.
    Sundaram S, Freemerman AJ, Johnson AR, Milner JJ, McNaughton KK, Galanko JA, Bendt KM, Darr DB, Perou CM, Troester MA, Makowski L (2013) Role of HGF in obesity-associated tumorigenesis: C3(1)-TAg mice as a model for human basal-like breast cancer. Breast Cancer Res Treat 142(3):489–503. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Yan L, Demars LC (2010) Effects of dietary fat on spontaneous metastasis of Lewis lung carcinoma in mice. Clin Exp Metastasis 27:581–590. CrossRefPubMedGoogle Scholar
  25. 25.
    Ortega FJ, Moreno-Navarrete JM, Mayas D, Garcia-Santos E, Gomez-Serrano M, Rodriguez-Hermosa JI, Ruiz B, Ricart W, Tinahones FJ, Fruhbeck G, Peral B, Fernandez-Real JM (2012) Breast cancer 1 (BrCa1) may be behind decreased lipogenesis in adipose tissue from obese subjects. PLoS One 7(5):e33233. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Yan L, Graef GL, Reeves PG, Johnson LK (2009) Selenium bioavailability from soy protein isolate and tofu in rats fed a torula yeast-based diet. J Agric Food Chem 57(24):11575–11580. CrossRefPubMedGoogle Scholar
  27. 27.
    Duffy MJ, O'Grady P, Devaney D, O’Siorain L, Fennelly JJ, Lijnen HJ (1988) Urokinase-plasminogen activator, a marker for aggressive breast carcinomas. Preliminary report. Cancer 62(3):531–533.<531::AID-CNCR2820620315>3.0.CO;2-B CrossRefPubMedGoogle Scholar
  28. 28.
    Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC Jr (2007) American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25(33):5287–5312. CrossRefPubMedGoogle Scholar
  29. 29.
    Gutierrez LS, Schulman A, Brito-Robinson T, Noria F, Ploplis VA, Castellino FJ (2000) Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1. Cancer Res 60(20):5839–5847.PubMedGoogle Scholar
  30. 30.
    Yan L, DeMars LC (2014) Effects of a high-fat diet on spontaneous metastasis of Lewis lung carcinoma in plasminogen activator inhibitor-1 deficient and wild-type mice. PLoS One 9(10):e110869. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Yan L, DeMars LC (2012) Dietary supplementation with methylseleninic acid, but not selenomethionine, reduces spontaneous metastasis of Lewis lung carcinoma in mice. Int J Cancer 131(6):1260–1266. CrossRefPubMedGoogle Scholar
  32. 32.
    Lebrecht A, Grimm C, Lantzsch T, Ludwig E, Hefler L, Ulbrich E, Koelbl H (2004) Monocyte chemoattractant protein-1 serum levels in patients with breast cancer. Tumour Biol 25(1–2):14–17. CrossRefPubMedGoogle Scholar
  33. 33.
    Cowen S, McLaughlin SL, Hobbs G, Coad J, Martin KH, Olfert IM, Vona-Davis L (2015) High-fat, high-calorie diet enhances mammary carcinogenesis and local inflammation in MMTV-PyMT mouse model of breast cancer. Cancers (Basel) 7(3):1125–1142. CrossRefGoogle Scholar
  34. 34.
    Cranford TL, Velazquez KT, Enos RT, Bader JE, Carson MS, Chatzistamou I, Nagarkatti M, Murphy EA (2017) Loss of monocyte chemoattractant protein-1 expression delays mammary tumorigenesis and reduces localized inflammation in the C3(1)/SV40Tag triple negative breast cancer model. Cancer Biol Ther:18(2): 85–93.
  35. 35.
    Yoshimura T, Howard OM, Ito T, Kuwabara M, Matsukawa A, Chen K, Liu Y, Liu M, Oppenheim JJ, Wang JM (2013) Monocyte chemoattractant protein-1/CCL2 produced by stromal cells promotes lung metastasis of 4T1 murine breast cancer cells. PLoS One 8(3):e58791. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Yan L, Combs GFJ (2014) Consumption of a high-fat diet abrogates inhibitory effects of methylseleninic acid on spontaneous metastasis of Lewis lung carcinoma in mice. Carcinogenesis 35(10):2308–2313. CrossRefPubMedGoogle Scholar
  37. 37.
    Hu Z, Fan C, Livasy C, He X, Oh DS, Ewend MG, Carey LA, Subramanian S, West R, Ikpatt F, Olopade OI, van de Rijn M, Perou CM (2009) A compact VEGF signature associated with distant metastases and poor outcomes. BMC Med 7:9. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Salcedo R, Ponce ML, Young HA, Wasserman K, Ward JM, Kleinman HK, Oppenheim JJ, Murphy WJ (2000) Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression. Blood 96(1):34–40.PubMedGoogle Scholar
  39. 39.
    Isogai C, Laug WE, Shimada H, Declerck PJ, Stins MF, Durden DL, Erdreich-Epstein A, DeClerck YA (2001) Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin. Cancer Res 61(14):5587–5594.PubMedGoogle Scholar
  40. 40.
    Chetrite GS, Cortes-Prieto J, Philippe JC, Wright F, Pasqualini JR (2000) Comparison of estrogen concentrations, estrone sulfatase and aromatase activities in normal, and in cancerous, human breast tissues. J Steroid Biochem Mol Biol 72(1–2):23–27. CrossRefPubMedGoogle Scholar
  41. 41.
    Brinton LA, Key TJ, Kolonel LN, Michels KB, Sesso HD, Ursin G, Van Den Eeden SK, Wood SN, Falk RT, Parisi D, Guillemette C, Caron P, Turcotte V, Habel LA, Isaacs CJ, Riboli E, Weiderpass E, Cook MB (2015) Prediagnostic sex steroid hormones in relation to male breast cancer risk. J Clin Oncol 33(18):2041–2050. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Takagi K, Moriya T, Kurosumi M, Oka K, Miki Y, Ebata A, Toshima T, Tsunekawa S, Takei H, Hirakawa H, Ishida T, Hayashi S, Kurebayashi J, Sasano H, Suzuki T (2013) Intratumoral estrogen concentration and expression of estrogen-induced genes in male breast carcinoma: comparison with female breast carcinoma. Horm Cancer 4(1):1–11. CrossRefPubMedGoogle Scholar
  43. 43.
    Gao R, Zhao L, Liu X, Rowan BG, Wabitsch M, Edwards DP, Nishi Y, Yanase T, Yu Q, Dong Y (2012) Methylseleninic acid is a novel suppressor of aromatase expression. J Endocrinol 212(2):199–205. CrossRefPubMedGoogle Scholar
  44. 44.
    Tworoger SS, Eliassen AH, Kelesidis T, Colditz GA, Willett WC, Mantzoros CS, Hankinson SE (2007) Plasma adiponectin concentrations and risk of incident breast cancer. J Clin Endocrinol Metab 92(4):1510–1516. CrossRefPubMedGoogle Scholar
  45. 45.
    Dieudonne MN, Bussiere M, Dos Santos E, Leneveu MC, Giudicelli Y, Pecquery R (2006) Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells. Biochem Biophys Res Commun 345(1):271–279. CrossRefPubMedGoogle Scholar
  46. 46.
    Wang Y, Lam JB, Lam KS, Liu J, Lam MC, Hoo RL, Wu D, Cooper GJ, Xu A (2006) Adiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. Cancer Res 66(23):11462–11470. CrossRefPubMedGoogle Scholar
  47. 47.
    Li GX, Lee HJ, Wang Z, Hu H, Liao JD, Watts JC, Combs GF Jr, Lu J (2008) Superior in vivo inhibitory efficacy of methylseleninic acid against human prostate cancer over selenomethionine or selenite. Carcinogenesis 29(5):1005–1012. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Wang L, Bonorden MJ, Li GX, Lee HJ, Hu H, Zhang Y, Liao JD, Cleary MP, Lu J (2009) Methyl-selenium compounds inhibit prostate carcinogenesis in the transgenic adenocarcinoma of mouse prostate model with survival benefit. Cancer Prev Res (Phila Pa) 2(5):484–495.CrossRefGoogle Scholar
  49. 49.
    Wang L, Guo X, Wang J, Jiang C, Bosland MC, Lu J, Deng Y (2016) Methylseleninic acid superactivates p53-senescence cancer progression barrier in prostate lesions of Pten-knockout mouse. Cancer Prev Res (Phila) 9(1):35–42. CrossRefGoogle Scholar
  50. 50.
    Sinha I, Null K, Wolter W, Suckow MA, King T, Pinto JT, Sinha R (2012) Methylseleninic acid downregulates hypoxia-inducible factor-1alpha in invasive prostate cancer. Int J Cancer 130(6):1430–1439. CrossRefPubMedGoogle Scholar

Copyright information

© US Government (outside the USA) 2017

Authors and Affiliations

  1. 1.U.S. Department of Agriculture, Agricultural Research ServiceGrand Forks Human Nutrition Research CenterGrand ForksUSA

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