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Polymorphism of cytosolic serine hydroxymethyltransferase, estrogen and breast cancer risk among Chinese women in Taiwan

  • Epidemiology
  • Published:
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Abstract

Cytosolic serine hydroxymethyltransferase (cSHMT) is key to intersection of folate-metabolic pathway, participating in the pyrimidine synthesis for DNA repair. Based on the hypothesis that variants of the cSHMT C1420T together with methionine synthase (MS A2756G) and 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) are associated with breast cancer, we performed a multigenic case–control study of the effects to breast cancer risk of four polymorphisms of folate-metabloizing genes against duration of estrogen exposure. Support of our hypothesis came from the following observations: (i) Allelic frequency of cSHMT C1420T was higher in the controls than in the cases, manifesting a 0.56-fold risk reduction in breast cancer (95%CI = 0.39–0.80); and this association was more significant in those women are susceptible to time of estrogen exposure. (ii) A joint effect of the cSHMT and MS polymorphisms significantly reduced susceptibility to breast cancer (aOR = 0.55; 95%CI = 0.34–0.88). (iii) There was a trend toward a reduced risk of breast cancer in women carrying a greater number of putative low-risk genotypes (P trend = 0.048). (iv) This synergistic effects on risk reduction was significantly interacted with length of estrogen exposure, exhibiting a longer time of estrogen exposure (≥30 years), menarche-to-FFTP interval (>11 years), age at the first full-term pregnancy (≤25 years), and body mass index (≤24). In conclusion, our study provides support to account for the preferential role of cSHMT polymorphism to lower risk of female breast cancer, and such reduced risk would be more significant in carriers with the polymorphisms of MS and MTHFR genes.

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Abbreviations

cSHMT :

Cytosolic serine hydroxymethyltransferase

MTHFR :

5,10-methylenetetrahydrofolate reductase

MS :

Methionine synthase

CE:

Catechol estrogen

FFTP:

First full-term pregnancy

BMI:

Body mass index

SNP:

Single nucleotide polymorphism

aOR:

Adjusted odds ratio

References

  1. Yager JD, Liehr JG (1996) Molecular mechanisms of estrogen carcinogenesis. Annu Rev Pharmacol Toxicol 36:203–232

    Article  PubMed  CAS  Google Scholar 

  2. Yang PS, Yang TL, Liu CL, Wu CW, Shen CY (1997) A case-control study of breast cancer in Taiwan–a low-incidence area. Br J Cancer 75:752–756

    PubMed  CAS  Google Scholar 

  3. Feigelson HS, Henderson BE (1996) Estrogens and breast cancer. Carcinogenesis 17:2279–2284

    Article  PubMed  CAS  Google Scholar 

  4. Rajapakse N, Butterworth M, Kortenkamp A (2005) Detection of DNA strand breaks and oxidized DNA bases at the single-cell level resulting from exposure to estradiol and hydroxylated metabolites. Environ Mol Mutagen 45:397–404

    Article  PubMed  CAS  Google Scholar 

  5. Zhang F, Swanson SM, van Breemen RB, Liu X, Yang Y, Gu C, Bolton JL (2001) Equine estrogen metabolite 4-hydroxyequilenin induces DNA damage in the rat mammary tissues: formation of single-strand breaks, apurinic sites, stable adducts, and oxidized bases. Chem Res Toxicol 14:1654–1659

    Article  PubMed  CAS  Google Scholar 

  6. Liehr JG (2001) Genotoxicity of the steroidal oestrogens oestrone and oestradiol: possible mechanism of uterine and mammary cancer development. Hum Reprod Update 7:273–281

    Article  PubMed  CAS  Google Scholar 

  7. Heil SG, Van der Put NM, Waas ET, den Heijer M, Trijbels FJ, Blom HJ (2001) Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects? Mol Genet Metab 73:164–172

    Article  PubMed  CAS  Google Scholar 

  8. Herbig K, Chiang EP, Lee LR, Hills J, Shane B, Stover PJ (2002) Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and S-adenosylmethionine biosyntheses. J Biol Chem 277:38381–38389

    Article  PubMed  CAS  Google Scholar 

  9. Skibola CF, Smith MT, Hubbard A, Shane B, Roberts AC, Law GR, Rollinson S, Roman E, Cartwright RA, Morgan GJ (2002) Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Blood 99:3786–3791

    Article  PubMed  CAS  Google Scholar 

  10. Hishida A, Matsuo K, Hamajima N, Ito H, Ogura M, Kagami Y, Taji H, Morishima Y, Emi N, Tajima K (2003) Associations between polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and susceptibility to malignant lymphoma. Haematologica 88:159–166

    PubMed  CAS  Google Scholar 

  11. Lomnytska M, Dubrovska A, Hellman U, Volodko N, Souchelnytskyi S (2006) Increased expression of cSHMT, Tbx3 and utrophin in plasma of ovarian and breast cancer patients. Int J Cancer 2006 118:412–421

    Article  CAS  Google Scholar 

  12. Wang Y, Guo W, He Y, Chen Z, Wen D, Zhang X, Wang N, Li Y, Ge H, Zhang J (2007) Association of MTHFR C677T and SHMT(1) C1420T with susceptibility to ESCC and GCA in a high incident region of Northern China. Cancer Causes Control 18:143–152

    Article  PubMed  CAS  Google Scholar 

  13. Sharp L, Little J (2004) Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol 159:423–443

    Article  PubMed  Google Scholar 

  14. Neumann AS, Lyons HJ, Shen H, Liu Z, Shi Q, Sturgis EM, Shete S, Spitz MR, El-Naggar A, Hong WK et al (2005) Methylenetetrahydrofolate reductase polymorphisms and risk of squamous cell carcinoma of the head and neck: a case-control analysis. Int J Cancer 115:131–136

    Article  PubMed  CAS  Google Scholar 

  15. Hur M, Park JY, Cho HC, Lee KM, Shin HY, Cho HI (2006) Methylenetetrahydrofolate reductase A1298C genotypes are associated with the risks of acute lymphoblastic leukaemia and chronic myelogenous leukaemia in the Korean population. Clin Lab Haematol 28:154–159

    Article  PubMed  CAS  Google Scholar 

  16. Pejchal R, Campbell E, Guenther BD, Lennon BW, Matthews RG, Ludwig ML (2006) Structural perturbations in the Ala → Val polymorphism of methylenetetrahydrofolate reductase: how binding of folates may protect against inactivation. Biochemistry 45:4808–4818

    Article  PubMed  CAS  Google Scholar 

  17. Todesco L, Angst C, Litynski P, Loehrer F, Fowler B, Haefeli WE (1999) Methylenetetrahydrofolate reductase polymorphism, plasma homocysteine and age. Eur J Clin Invest 29:1003–1009

    Article  PubMed  CAS  Google Scholar 

  18. Weisberg IS, Jacques PF, Selhub J, Bostom AG, Chen Z, Curtis Ellison R, Eckfeldt JH, Rozen R (2001) The 1298A → C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. Atherosclerosis 156:409–415

    Article  PubMed  CAS  Google Scholar 

  19. Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G, Wickramasinghe SN, Everson RB, Ames BN (1999) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci USA 94:3290–3295

    Article  Google Scholar 

  20. Ma J, Stampfer MJ, Christensen B, Giovannucci E, Hunter DJ, Chen J, Willett WC, Selhub J, Hennekens CH, Gravel R et al (1999) A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 8:825–829

    PubMed  CAS  Google Scholar 

  21. Cavalieri E, Frenkel K, Liehr JG, Rogan E, Roy D (2000) Estrogens as endogenous genotoxic agents—DNA adducts and mutations. J Natl Cancer Inst 27:75–93

    CAS  Google Scholar 

  22. Pike MC, Spicer DV, Dahmoush L, Press MF (1993) Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev 15:17–35

    PubMed  CAS  Google Scholar 

  23. Fang JY, Xiao SD (2003) Folic acid, polymorphism of methyl-group metabolism genes, and DNA methylation in relation to GI carcinogenesis. J Gastroenterol 38:821–829

    Article  PubMed  CAS  Google Scholar 

  24. Rohan TE, Jain MG, Howe GR, Miller AB (2000) Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 92:266–269

    Article  PubMed  CAS  Google Scholar 

  25. Sharp L, Little J, Schofield AC, Pavlidou E, Cotton SC, Miedzybrodzka Z, Baird JO, Haites NE, Heys SD, Grubb DA (2002) Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR). Cancer Lett 181:65–71

    Article  PubMed  CAS  Google Scholar 

  26. Huang CS, Shen CY, Chang KJ, Hsu SM, Chern HD (1999) Cytochrome P4501A1 polymorphism as a susceptibility factor for breast cancer in postmenopausal Chinese women in Taiwan. Br J Cancer 80:1838–1843

    Article  PubMed  CAS  Google Scholar 

  27. Lo YL, Yu JC, Huang CS, Tseng SL, Chang TM, Chang KJ, Wu CW, Shen CY (1998) Allelic loss of the BRCA1 and BRCA2 genes and other regions on 17q and 13q in breast cancer among women from Taiwan (area of low incidence but early onset). Int J Cancer 79:580–587

    Article  PubMed  CAS  Google Scholar 

  28. Lou MA, Tseng SL, Chang SF, Yue CT, Chang BL, Chou CH, Yang SL, Teh BH, Wu CW, Shen CY (1997) Novel patterns of p53 abnormality in breast cancer from Taiwan: experience from a low-incidence area. Br J Cancer 75:746–751

    PubMed  CAS  Google Scholar 

  29. Shen CY, Yu JC, Lo YL, Kuo CH, Yue CT, Jou YS, Huang CS, Lung JC, Wu CW (2000) Genome-wide search for loss of heterozygosity using laser capture microdissected tissue of breast carcinoma: an implication for mutator phenotype and breast cancer pathogenesis. Cancer Res 60:3884–3892

    PubMed  CAS  Google Scholar 

  30. Huang CS, Chern HD, Shen CY, Hsu SM, Chang KJ (1999) Association between N-acetyltransferase 2 (NAT2) genetic polymorphism and development of breast cancer in post-menopausal Chinese women in Taiwan, an area of great increase in breast cancer incidence. Int J Cancer 82:175–179

    Article  PubMed  CAS  Google Scholar 

  31. Yang HC, Lin CH, Hung SI, Fann CS (2006) A comparison of individual genotyping and pooled DNA analysis for polymorphism validation prior to large-scale genetic studies. Ann Hum Genet 70(Pt 3):350–359

    Article  PubMed  CAS  Google Scholar 

  32. Cheng TC, Chen ST, Huang CS, Fu YP, Yu JC, Cheng CW, Wu PE, Shen CY (2005) Breast cancer risk associated with genotype polymorphism of the catechol estrogen-metabolizing genes: a multigenic study on cancer susceptibility. Int J Cancer 113:345–353

    Article  PubMed  CAS  Google Scholar 

  33. Fu YP, Yu JC, Cheng TC, Lou MA, Hsu GC, Wu CY, Chen ST, Wu HS, Wu PE, Shen CY (2003) Breast cancer risk associated with genotypic polymorphism of the nonhomologous end-joining genes: a multigenic study on cancer susceptibility. Cancer Res 63:2440–2446

    PubMed  CAS  Google Scholar 

  34. Huang CS, Chern HD, Chang KJ, Cheng CW, Hsu SM, Shen CY (1999) Breast cancer risk associated with genotype polymorphism of the estrogen-metabolizing genes CYP17, CYP1A1, and COMT: a multigenic study on cancer susceptibility. Cancer Res 59:4870–4875

    PubMed  CAS  Google Scholar 

  35. Lo YL, Yu JC, Chen ST, Yang HC, Fann CS, Mau YC, Shen CY (2005) Breast cancer risk associated with genotypic polymorphism of the mitosis-regulating gene Aurora-A/STK15/BTAK. Int J Cancer 115:276–283

    Article  PubMed  CAS  Google Scholar 

  36. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113

    Article  PubMed  CAS  Google Scholar 

  37. Botto LD, Khoury MJ (2001) Commentary: facing the challenge of gene-environment interaction: the two-by-four table and beyond. Am J Epidemiol 153:1016–1020

    Article  PubMed  CAS  Google Scholar 

  38. Russo J, Tay LK, Russo IH (1982) Differentiation of the mammary gland and susceptibility to carcinogenesis. Breast Cancer Res Treat 2:5–73

    Article  PubMed  CAS  Google Scholar 

  39. van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van den Heuvel LP, Mariman EC, den Heyer M, Rozen R, Blom HJ (1995) Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 346:1070–1071

    Article  PubMed  Google Scholar 

  40. Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B, Ross M, Eydoux P, Rosenblatt DS, Rozen R, Gravel RA (1996) Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Hum Mol Genet 5:1867–1874

    Article  PubMed  CAS  Google Scholar 

  41. Relton CL, Wilding CS, Laffling AJ, Jonas PA, Burgess T, Binks K, Tawn EJ, Burn J (2004) Low erythrocyte folate status and polymorphic variation in folate-related genes are associated with risk of neural tube defect pregnancy. Mol Genet Metab 81:273–281

    Article  PubMed  CAS  Google Scholar 

  42. Relton CL, Wilding CS, Pearce MS, Laffling AJ, Jonas PA, Lynch SA, Tawn EJ, Burn J (2004) Gene-gene interaction in folate-related genes and risk of neural tube defects in a UK population. J Med Genet 41:256–260

    Article  PubMed  CAS  Google Scholar 

  43. Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Jin F, Zheng W (2006) MTR and MTRR polymorphisms, dietary intake, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 15:586–588

    Article  PubMed  CAS  Google Scholar 

  44. Justenhoven C, Hamann U, Pierl CB, Rabstein S, Pesch B, Harth V, Baisch C, Vollmert C, Illig T, Bruning T et al (2005) One-carbon metabolism and breast cancer risk: no association of MTHFR, MTR, and TYMS polymorphisms in the GENICA study from Germany. Cancer Epidemiol Biomarkers Prev 14:3015–3018

    Article  PubMed  CAS  Google Scholar 

  45. Lissowska J, Gaudet MM, Brinton LA, Chanock SJ, Peplonska B, Welch R, Zatonski W, Szeszenia-Dabrowska N, Park S, Sherman M et al (2007) Genetic polymorphisms in the one-carbon metabolism pathway and breast cancer risk: a population-based case-control study and meta-analyses. Intl J Cancer 120:2696–2703

    Article  CAS  Google Scholar 

  46. Skibola CF, Forrest MS, Coppede F, Agana L, Hubbard A, Smith MT, Bracci PM, Holly EA (2004) Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. Blood 104:2155–2162

    Article  PubMed  CAS  Google Scholar 

  47. Jones PA, Takai D (2001) The role of DNA methylation in mammalian epigenetics. Science 293:1068–1070

    Article  PubMed  CAS  Google Scholar 

  48. Lucock M (2000) Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Mol Genet Metab 71:121–138

    Article  PubMed  CAS  Google Scholar 

  49. Hekim N, Ergen A, Yaylim I, Yilmaz H, Zeybek U, Ozturk O, Isbir T (2007) No association between methylenetetrahydrofolate reductase C677T polymorphism and breast cancer. Cell Biochem Funct 25:115–117

    Article  PubMed  CAS  Google Scholar 

  50. Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Hebert JR, Jin F, Zheng W (2004) MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Epidemiol Biomarkers Prev 13:190–196

    Article  PubMed  CAS  Google Scholar 

  51. Gershoni-Baruch R, Dagan E, Israeli D, Kasinetz L, Kadouri E, Friedman E (2000) Association of the C677T polymorphism in the MTHFR gene with breast and/or ovarian cancer risk in Jewish women. Eur J Cancer 36:2313–2316

    Article  PubMed  CAS  Google Scholar 

  52. Baglietto L, English DR, Gertig DM, Hopper JL, Giles GG (2005) Does dietary folate intake modify effect of alcohol consumption on breast cancer risk? Prospective cohort study. BMJ 331:807

    Article  PubMed  CAS  Google Scholar 

  53. Le Marchand L, Haiman CA, Wilkens LR, Kolonel LN, Henderson BE (2004) MTHFR polymorphisms, diet, HRT, and breast cancer risk: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev 13:2071–2077

    PubMed  CAS  Google Scholar 

  54. Pisha E, Lui X, Constantinou AI, Bolton JL (2001) Evidence that a metabolite of equine estrogens, 4-hydroxyequilenin, induces cellular transformation in vitro. Chem Res Toxicol 14:82–90

    Article  PubMed  CAS  Google Scholar 

  55. Matsui A, Ikeda T, Enomoto K, Hosoda K, Nakashima H, Omae K, Watanabe M, Hibi T, Kitajima M (2000) Increased formation of oxidative DNA damage, 8-hydroxy-2′-deoxyguanosine, in human breast cancer tissue and its relationship to GSTP1 and COMT genotypes. Cancer Lett 15:87–95

    Article  Google Scholar 

  56. Clayton D, McKeigue PM (2001) Epidemiological methods for studying genes and environmental factors in complex diseases. Lancet 358:1356–1360

    Article  PubMed  CAS  Google Scholar 

  57. Cordell HJ (2002) Epistasis: what it means, what it doesn’t mean, and statistical methods to detect it in humans. Hum Mol Genet 11:2463–2468

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Show-Lin Yang and Chung-Pei Cheng for assistance in organizing our study, and we are also grateful to all of the study participants for their works.

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Authors and Affiliations

  1. Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, 402, Taiwan

    Chun-Wen Cheng

  2. Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

    Jyh-Cherng Yu

  3. Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan

    Chiun-Sheng Huang

  4. Department of Biomedical Sciences, Chung-Shan Medical University, Taichung, Taiwan

    Jia-Ching Shieh

  5. Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan

    Yi-Ping Fu, Hsiao-Wei Wang, Pei-Ei Wu & Chen-Yang Shen

  6. Graduate Institute of Environmental Science, China Medical University, Taichung, 40402, Taiwan

    Chen-Yang Shen

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  1. Chun-Wen Cheng
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Correspondence to Chun-Wen Cheng or Chen-Yang Shen.

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Cheng, CW., Yu, JC., Huang, CS. et al. Polymorphism of cytosolic serine hydroxymethyltransferase, estrogen and breast cancer risk among Chinese women in Taiwan. Breast Cancer Res Treat 111, 145–155 (2008). https://doi.org/10.1007/s10549-007-9754-x

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  • DOI: https://doi.org/10.1007/s10549-007-9754-x

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