Publishing house Radiotekhnika

"Publishing house Radiotekhnika":
scientific and technical literature.
Books and journals of publishing houses: IPRZHR, RS-PRESS, SCIENCE-PRESS

Тел.: +7 (495) 625-9241


Metabolism of homocystein and cystein role in breast cancer


N.E. Kushlinskii – Dr.Sc. (Med.), Professor, Member-Correspondent of Russian Academy of Sciences, N.N. Blokhin National Medical Cancer Research Center (Moscow)
E.I. Alekseeva – Post-Graduate Student, N.N. Blokhin National Medical Cancer Research Center (Moscow)
A.V. Ivanov – Ph.D. (Biol.), Institute of General Pathology and Pathophysiology (Moscow)
E.A. Avilova – Ph.D. (Med.), N.N. Blokhin National Medical Cancer Research Center (Moscow)
E.S. Gershtein – Dr.Sc. (Biol.), Professor, N.N. Blokhin National Medical Cancer Research Center (Moscow)
A.A. Kubatiev – Dr.Sc. (Med.), Professor, Academician of Russian Academy of Sciences, Institute of General Pathology and Pathophysiology (Moscow)

Interest in studying metabolic characteristics of thiol-containing amino acids (cysteine and homocysteine) in breast cancer is imposed by the ongoing search for new biomarkers and therapeutic approaches, such as metabolic starvation. This re-view describes the role of metabolic pathways (methionine cycle and transsulfuration) in mammary gland carcinogenesis, as well as the prospects of cysteine and homocysteine application in clinical and laboratory diagnostics of breast cancer. Despite the fact that the metabolism of these amino acids in this pathology has been actively studied for more than a dec-ade and numerous studies have shown their important role in breast cancer development, the results of clinical trials are contradictory.

  1. Siegel R., Naishadham D., Jemal A. Cancer statistics, 2013 // CA Cancer J. Clin. 2013. V. 63. № 1. Р. 1130.
  2. Ferlay J., Soerjomataram I., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012 // Int. J. Cancer. 2015. V. 136. № 5. Р. E359386.
  3. Lukong K.E. Understanding breast cancer  the long and winding road // BBA Clin. 2017. № 7. Р. 6477.
  4. González-Jiménez E., García P.A., Aguilar M.J., Padilla C.A., Álvarez J. Breastfeeding and the prevention of breast cancer: a retrospective review of clinical histories // J. Clin. Nurs. 2014. V. 23. № 17-18. Р. 23972403.
  5. DeSantis C.E., Bray F., Ferlay J., Lortet-Tieulent J., Anderson B.O., Jemal A. International Variation in Female Breast Cancer Incidence and Mortality Rates // Cancer Epidemiol. Biomarkers Prev. 2015. V. 24. № 10. Р. 14951506.
  6. Key T., Appleby P., Barnes I., Reeves G. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies // J. Natl. Cancer Inst. 2002. V. 94. № 8. Р. 606616.
  7. Fox E.M., Andrade J., Shupnik M.A. Novel actions of estrogen to promote proliferation: integration of cytoplasmic and nuclear pathways // Steroids. 2009. V. 74. № 7. Р. 622627.
  8. Kushner P.J., Agard D.A., Greene G.L., Scanlan T.S., Shiau A.K., Uht R.M., Webb P. Estrogen receptor pathways to AP-1 // J. Steroid Biochem. Mol. Biol. 2000. V. 74. № 5. Р. 311317.
  9. Aquila S., Sisci D., Gentile M., Middea E., Catalano S., Carpino A., Rago V., Andò S. Estrogen receptor (ER)alpha and ER beta are both expressed in human ejaculated spermatozoa: evidence of their direct interaction with phosphatidylinositol-3-OH kinase/Akt pathway // J. Clin. Endocrinol. Metab. 2004. V. 89. № 3. Р. 14431451.
  10. Carroll J.S. Mechanisms of oestrogen receptor (ER) gene regulation in breast cancer // Eur. J. Endocrinol. 2016. V. 175. № 1. Р. R4149.
  11. Duffy M.J., Harbeck N., Nap M., Molina R., Nicolini A., Senkus E., Cardoso F. Clinical use of biomarkers in breast cancer: Updated guidelines from the European Group on Tumor Markers (EGTM) // Eur. J. Cancer. 2017. № 75. Р. 284298.
  12. Minatani N., Waraya M., Yamashita K., Kikuchi M., Ushiku H., Kojo K., Ema A., Nishimiya H., Kosaka Y., Katoh H., Sengoku N., Tanino H., Sidransky D., Watanabe M. Prognostic Significance of Promoter DNA Hypermethylation of cysteine dioxygenase 1 (CDO1) Gene in Primary Breast Cancer // PLoS One. 2016. V. 11. № 1. Р. e0144862.
  13. Krasil'nikov M.A. Sovremennye podhody k izucheniju mehanizma jestrogen nezavisimogo rosta opuholej molochnoj zhelezy // Voprosy onkologii. 2004. T. 50. S. 399405.
  14. Biologichesskie markery' opuxolej: fundamental'ny'e i klinicheskie itssledovaniya / Pod red. N.E. Kushlinskogo i M.A. Krasil'nikova. M.: Izd-vo RAMN. 2017.632 s.
  15. Normanno N., Di Maio M., De Maio E., De Luca A., de Matteis A., Giordano A., Perrone F. Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer // Endocr. Relat. Cancer. 2005. V. 12. № 4. Р. 721747.
  16. Clarke R., Liu M.C., Bouker K.B., Gu Z., Lee R.Y., Zhu Y., Skaar T.C., Gomez B., O'Brien K., Wang Y., Hilakivi-Clarke L.A. Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling // Oncogene. 2003. № 22. Р. 73167339.
  17. Jordan V.C. Targeting antihormone resistance in breast cancer: a simple solution // Ann. Oncol. 2003. V. 14. № 7. Р. 969970.
  18. Henderson B.E., Ponder B.A.J., Ross R.K. Hormones, Genes and Cancer. New York: Oxford University Press. 2003. Р. 120–139.
  19. Kuukasjärvi T., Kononen J., Helin H., Holli K., Isola J. Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy // J. Clin. Oncol. 1996. V. 14. № 9. Р. 25842589.
  20. Song G., Ouyang G., Bao S. The activation of Akt/PKB signaling pathway and cell survival // J. Cell. Mol. Med. 2005. V. 9. № 1. Р. 5971.
  21. Thomas R.S., Sarwar N., Phoenix F., Coombes R.C., Ali S. Phosphorylation at serines 104 and 106 by Erk1/2 MAPK is important for estrogen receptor-alpha activity // J. Mol. Endocrinol. 2008. V. 40. № 4. Р. 173184.
  22. Kok M., Zwart W., Holm C., Fles R., Hauptmann M., Van't Veer L.J., Wessels L.F., Neefjes J., Stål O., Linn S.C., Landberg G., Michalides R. PKA-induced phosphorylation of ERα at serine 305 and high PAK1 levels is associated with sensitivity to tamoxifen in ER-positive breast cancer // Breast Cancer Res. Treat. 2011. V. 125. № 1. Р. 1–12.
  23. Avilova E.A., Andreeva O.E., Shatskaia V.A., Krasil'nikov M.A. The role of protein kinase PAK1 in the regulation of estrogen-independent growth of breast cancer // Biochemistry (Moscow) Supplement Series B: Biomed. Chem. 2015. V. 9. № 1. Р. 58–62.
  24. Geck R.C., Toker A. Nonessential amino acid metabolism in breast cancer // Adv. Biol. Regul. 2016. № 62. Р. 1117.
  25. Martinez-Outschoorn U.E., Peiris-Pagés M., Pestell R.G., Sotgia F., Lisanti M.P. Cancer metabolism: a therapeutic perspective // Nat. Rev. Clin. Oncol. 2017. V. 14. № 1. Р. 1131.
  26. Morandi A., Chiarugi P. Metabolic implication of tumor:stroma crosstalk in breast cancer // J. Mol. Med. (Berl). 2014. V. 92. № 2. Р. 117126.
  27. Budczies J., Denkert C. Tissue-Based Metabolomics to Analyze the Breast Cancer Metabolome // Recent Results Cancer Res. 2016. № 207. Р. 157175.
  28. Hoffman R.M. Development of recombinant methioninase to target the general cancer-specific metabolic defect of methionine dependence: a 40-year odyssey // Exp. Opin. Biol. Ther. 2015. V.15. № 1. Р. 21-31.
  29. Guo H., Lishko V.K., Herrera H., Groce A., Kubota T., Hoffman R.M. Therapeutic tumor-specific cell cycle block induced by methionine starvation in vivo // Cancer Res. 1993. V. 53. №23. Р. 56765679.
  30. Lu S.C., Mato J.M. S-adenosylmethionine in liver health, injury, and cancer // Physiol. Rev. 2012. V. 92. № 4. Р. 15151542.
  31. del Pino M.M., Corrales F.J., Mato J.M. Hysteretic behavior of methionine adenosyltransferase III. Methionine switches between two conformations of the enzyme with different specific activity // J. Biol. Chem. 2000. V. 275. № 31. Р. 2347623482.
  32. Hershfield M.S., Kredich N.M., Koller C.A., Mitchell B.S., Kurtzberg J., Kinney T.R., Falletta J.M. S-adeno¬syl¬ho¬mocysteine catabolism and basis for acquired resistance during treatment of T-cell acute lymphoblastic leukemia with 2'-deoxyco¬for¬mycin alone and in combination with 9-beta-D-arabinofuranosyladenine // Cancer Res. 1983. V. 43. № 7. Р. 34513458.
  33. Park S.J., Kong H.K., Kim Y.S., Lee Y.S., Park J.H. Inhibition of S-adenosylhomocysteine hydrolase decreases cell mobility and cell proliferation through cell cycle arrest // Am. J. Cancer Res. 2015. V. 5. № 7. Р. 21272138.
  34. Strizhevskaja A.M., Senzhapova Je.R., Dzampaev A.Z., Bajkova V.N. Potencial'nyj kriterij farmakodinamicheskogo jeffekta vysokih doz metotreksata – gomocistein // Patologicheskaja fiziologija i jeksperimental'naja terapija. 2014. № 2. S. 4044.
  35. Finkelstein J.D. Methionine metabolism in mammals // J. Nutr. Biochem. 1990. V. 1. № 5. Р. 228–237.
  36. Peyrin-Biroulet L., Rodriguez-Gúeant R.M., Cha¬mail¬lard M., Desreumaux P., Xia B., Bronowicki J.P., Bigard M.A., Gúeant J.L. Vascular and cellular stress in inflammatory bowel disease: revisiting the role of homocysteine // Am. J. Gastroenterol. 2007. № 102. Р. 11081115.
  37. Zhu B.T. Medical hypothesis: hyperhomocysteinemia is a risk factor for estrogen-induced hormonal cancer // Int. J. Oncol. 2003. V. 22. № 3. Р. 499508.
  38. Wu X., Zou T., Cao N., Ni J., Xu W., Zhou T., Wang X. Plasma homocysteine levels and genetic polymorphisms in folate metablism are associated with breast cancer risk in chinese women // Hered. Cancer Clin. Pract. 2014. V. 12. № 1. Р. 2. doi: 10.1186/1897-4287-12-2.
  39. Henderson B.E., Ross R., Bernstein L. Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation award lecture // Cancer Res. 1988. V. 48. № 2. Р. 246253.
  40. Goodman J.E., Lavigne J.A., Wu K., Hel¬zlsouer K.J., Strickland P.T., Selhub J., Yager J.D. COMT genotype, micronutrients in the folate metabolic pathway and breast cancer risk // Carcinogenesis (Lond.). 2001. V. 22. № 10. Р. 16611665.
  41. Ratter F., Gassner C., Shatrov V., Lehmann V. Modulation of tumor necrosis factor-alpha-mediated cytotoxicity by changes of the cellular methylation state: mechanism and in vivo relevance // Int. Immunol. 1999. № 11. Р. 519527.
  42. Naushad S.M., Hussain T., Al-Attas O.S., Prayaga A., Digumarti R.R., Gottumukkala S.R., Kutala V.K. Molecular insights into the association of obesity with breast cancer risk: relevance to xenobiotic metabolism and CpG island methylation of tumor suppressor genes // Mol. Cell. Biochem. 2014. V. 392. № 12. Р. 273280.
  43. Mato J.M., Alvarez L., Ortiz P., Pajares M.A. S-adenosylmethionine synthesis: molecular mechanisms and clinical implications // Pharmacol. Ther. 1997. V. 73. № 3. Р. 265280.
  44. Prudova A., Bauman Z., Braun A., Vitvitsky V., Lu S.C., Banerjee R. S-adenosylmethionine stabilizes cystathionine beta-synthase and modulates redox capacity // Proc. Natl. Acad. Sci. USA. 2006. V. 103. № 17. Р. 64896494.
  45. Stipanuk M.H., Ueki I. Dealing with methionine/homocysteine sulfur: cysteine metabolism to taurine and inorganic sulfur // J. Inherit. Metab. Dis. 2011. V. 34. № 1. Р. 1732.
  46. Hildebrandt T.M., Grieshaber M.K. Three enzymatic activities catalyze the oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria // FEBS J. 2008. № 275. Р. 3352–3361.
  47. Feng C., Tollin G., Enemark J.H. Sulfite oxidizing enzymes // Biochim. Biophys. Acta. 2007. № 1774. Р. 527–539.
  48. Dominy J.E. Jr., Hwang J., Guo S., Hirschberger L.L., Zhang S., Stipanuk M.H. Synthesis of amino acid cofactor in cysteine dioxygenase is regulated by substrate and represents a novel post-translational regulation of activity // J. Biol. Chem. 2008. V. 283. № 18. Р. 1218812201.
  49. Al-Awadi F., Yang M., Tan Y., Han Q., Li S., Hoffman R.M. Human tumor growth in nude mice is associated with decreased plasma cysteine and homocysteine // Anticancer Res. 2008. V. 28. № 5A. Р. 25412544.
  50. Jeschke J., O'Hagan H.M., Zhang W., Vatapalli R., Calmon M.F., Danilova L., Nelkenbrecher C., Van Neste L., Bijsmans I.T., Van Engeland M., Gabrielson E., Schuebel K.E., Winterpacht A., Baylin S.B., Herman J.G., Ahuja N. Frequent inactivation of cysteine dioxygenase type 1 contributes to survival of breast cancer cells and resistance to anthracyclines // Clin. Cancer Res. 2013. V. 19. № 12. Р. 32013211.
  51. Minatani N., Waraya M., Yamashita K., Kikuchi M., Ushiku H., Kojo K., Ema A., Nishimiya H., Kosaka Y., Katoh H., Sengoku N., Tanino H., Sidransky D., Watanabe M. Prognostic Significance of Promoter DNA Hypermethylation of cysteine dioxygenase 1 (CDO1) Gene in Primary Breast Cancer // PLoS One. 2016. V. 11. № 1. Р. e0144862.
  52. Sen S., Kawahara B., Gupta D., Tsai R., Khachatryan M., Roy-Chowdhuri S., Bose S., Yoon A., Faull K., Farias-Eisner R., Chaudhuri G. Role of cystathionine β-synthase in human breast cancer // Free Radic. Biol. Med. 2015. № 86. Р. 228238.
  53. Lo M., Wang Y.-Z., Gout P.W. The xc- cystine/glu¬tamate antiporter: A potential target for therapy of cancer and other diseases // J. Cell. Physiol. 2008. № 215. Р. 593–602.
  54. Zhang S.M., Willett W.C., Selhub J., Manson J.E., Colditz G.A., Hankinson S.E. Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer // J. Natl. Cancer. Inst. 2003. V. 95. № 5. Р. 373380.
  55. Yang Y., Yee D. IGF-I regulates redox status in breast cancer cells by activating the amino acid transport molecule xC- // Cancer Res. 2014. V. 74. № 8. Р. 22952305.
  56. Habib E., Linher-Melville K., Lin H.X., Singh G. Expression of xCT and activity of system xc(-) are regulated by NRF2 in human breast cancer cells in response to oxidative stress // Redox Biol. 2015. № 5. Р. 3342.
  57. Slosky L.M., BassiriRad N.M., Symons A.M., Thompson M., Doyle T., Forte B.L., Staatz W.D., Bui L., Neumann W.L., Mantyh P.W., Salvemini D., Largent-Milnes T.M., Vanderah T.W. The cystine/glu¬tamate antiporter system xc- drives breast tumor cell glutamate release and cancer-induced bone pain // Pain. 2016. V. 157. № 11. Р. 26052616.
  58. Ferroni P., Palmirotta R., Martini F., Riondino S., Savonarola A., Spila A., Ciatti F., Sini V., Mariotti S., Del Monte G., Roselli M., Guadagni F. Determinants of homocysteine levels in colorectal and breast cancer patients // Anticancer Res. 2009. V. 29. № 10. Р. 41314138.
  59. Gatt A., Makris A., Cladd H., Burcombe R.J., Smith J.M., Cooper P., Thompson D., Makris M. Hyperhomocysteinemia in women with advanced breast cancer // Int. J. Lab. Hematol. 2007. V. 29. № 6. Р. 421425.
  60. Chou Y.C., Lee M.S., Wu M.H., Shih H.L., Yang T., Yu C.P., Yu J.C., Sun C.A. Plasma homocysteine as a metabolic risk factor for breast cancer: findings from a case-control study in Taiwan // Breast Cancer Res. Treat. 2007. V. 101. № 2. Р. 199205.
  61. Yoshihara R.N., Teixeira B.M., Adami F., Kuniyoshi R.K., Alves B.C., Gehrke F.S., Vilas-Bôas V.A., Azzalis L.A., Junqueira V.B., Pereira E.C., Fonseca F.L. Circulating tumor cell detection during chemotherapy in patients with breast cancer is not associated with plasma homocysteine levels // Tumour Biol. 2013. V. 34. № 5. Р. 29372941.
  62. Agnoli C., Grioni S., Krogh V., Pala V., Allione A., Matullo G., Di Gaetano C., Tagliabue G., Pedraglio S., Garrone G., Cancarini I., Cavalleri A., Sieri S. Plasma Riboflavin and Vitamin B-6, but Not Homocysteine, Folate, or Vitamin B-12, Are Inversely Associated with Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition-Varese Cohort // J. Nutr. 2016. V. 146. № 6. Р. 12271234.
  63. Lin J., Lee I.M., Song Y., Cook N.R., Selhub J., Manson J.E., Buring J.E., Zhang S.M. Plasma homocysteine and cysteine and risk of breast cancer in women // Cancer Res. 2010. V. 70. № 6. Р. 23972405.
  64. Goodman J.E., Lavigne J.A., Wu K., Helzlsouer K.J., Strickland P.T., Selhub J., Yager J.D. COMT genotype, micronutrients in the folate metabolic pathway and breast cancer risk // Carcinogenesis (Lond.). 2001. V. 22. № 10. Р. 16611665.
  65. Song A., Zhao L., Li Y., Wu L., Li Y., Liu X., Lan S. Haplotypes of the MTHFR gene are associated with an increased risk of breast cancer in a Han Chinese population in Gansu province // IUBMB Life. 2016. V. 68. № 7. Р. 526534.
  66. Ryu C.S., Kwak H.C., Lee K.S., Kang K.W., Oh S.J., Lee K.H., Kim H.M., Ma J.Y., Kim S.K. Sulfur amino acid metabolism in doxorubicin-resistant breast cancer cells // Toxicol. Appl. Pharmacol. 2011. № 255. Р. 94–102.
June 24, 2020
May 29, 2020

© Издательство «РАДИОТЕХНИКА», 2004-2017            Тел.: (495) 625-9241                   Designed by [SWAP]Studio