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Tumor Biology

, Volume 35, Issue 5, pp 4757–4764 | Cite as

Transforming growth factor beta1 (TGFβ1) polymorphisms and breast cancer risk

  • Davar Amani
  • Ahad Khalilnezhad
  • Abbas Ghaderi
  • Norrio Niikawa
  • Ko-ichiro Yoshiura
Research Article

Abstract

Transforming growth factor β1 (TGFβ1) is suggested to be involved in the pathogenesis of and in complications with breast cancer (BC). Polymorphisms in TGFβ1 gene (TGFβ1) have been suggested by many investigators to have a role in susceptibility to BC; however, many discordant data have been reported. Considering the role of ethnic variations, we performed an association study between TGFβ1 polymorphisms and BC among Iranian women. We sequenced DNA samples of 110 BC and 110 normal control women for the exons and their adjacent intronic regions of TGFβ1 using PCR. The allele, genotype, and haplotype frequencies were calculated using PowerMarker V3.25 and R 3.0.2 softwares. Ten single nucleotide polymorphisms (SNPs) were detected. Statistical analysis on the frequency of seven most frequent SNPs, including the three coding SNPs (cSNPs) revealed no significant difference between BC and control women. Moreover, among 11 constructed haplotypes, “GTGCCGC” was significantly different between two study groups. In conclusion, we found no association between the studied SNPs of TGFβ1 and BC among Iranian women, but a possible association between “GTGCCGC” haplotype and BC was seen. However, further studies are suggested to clarify this association.

Keywords

Breast cancer Gene polymorphism Haplotype Iran Transforming growth factor beta 

Notes

Acknowledgments

This study was financially supported by Shiraz University of Medical Sciences and in a part by Shiraz Institute for Cancer Research. The sequencing of TGFβ1 gene was done in the Department of Human Genetics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

Conflicts of interest

The authors declare that there is no conflict of interest.

References

  1. 1.
    Porter PL. Global trends in breast cancer incidence and mortality. Salud Publica Mex. 2009;51:s141–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Ikushima H, Miyazono K. TGFbeta signaling: a complex web in cancer progression. Nat Rev Cancer. 2010;10:415–24.CrossRefPubMedGoogle Scholar
  3. 3.
    Marcoe JP, Lim JR, Schaubert KL, Fodil-Cornu N, Matka M, McCubbrey AL, et al. TGF-beta is responsible for NK cell immaturity during ontogeny and increased susceptibility to infection during mouse infancy. Nat Immunol. 2012Google Scholar
  4. 4.
    Ling E, Robinson DS. Transforming growth factor-beta1: its anti-inflammatory and pro-fibrotic effects. Clin Exp Allergy. 2002;32:175–8.CrossRefPubMedGoogle Scholar
  5. 5.
    van Meeteren LA, ten Dijke P. Regulation of endothelial cell plasticity by TGF-beta. Cell Tissue Res. 2012;347:177–86.CrossRefPubMedGoogle Scholar
  6. 6.
    Ikushima H, Miyazono K. Biology of transforming growth factor-beta signaling. Curr Pharm Biotechnol. 2011;12:2099–107.CrossRefPubMedGoogle Scholar
  7. 7.
    Fujii D, Brissenden JE, Derynck R, Francke U. Transforming growth factor beta gene maps to human chromosome 19 long arm and to mouse chromosome 7. Somat Cell Mol Genet. 1986;12:281–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Wakefield LM, Piek E, Bottinger EP. TGF-beta signaling in mammary gland development and tumorigenesis. J Mammary Gland Biol Neoplasia. 2001;6:67–82.CrossRefPubMedGoogle Scholar
  9. 9.
    Babyshkina N, Malinovskaya E, Stakheyeva M, Volkomorov V, Slonimskaya E, Maximov V, et al. Association of functional −509C>T polymorphism in the TGF-beta1 gene with infiltrating ductal breast carcinoma risk in a Russian Western Siberian population. Cancer Epidemiol. 2011;35:560–3.CrossRefPubMedGoogle Scholar
  10. 10.
    Woo SU, Park KH, Woo OH, Yang DS, Kim AR, Lee ES, et al. Association of a TGF-beta1 gene −509 C/T polymorphism with breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2010;124:481–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Dunning AM, Ellis PD, McBride S, Kirschenlohr HL, Healey CS, Kemp PR, et al. A transforming growth factorbeta1 signal peptide variant increases secretion in vitro and is associated with increased incidence of invasive breast cancer. Cancer Res. 2003;63:2610–5.PubMedGoogle Scholar
  12. 12.
    Shin A, Shu XO, Cai Q, Gao YT, Zheng W. Genetic polymorphisms of the transforming growth factor-beta1 gene and breast cancer risk: a possible dual role at different cancer stages. Cancer Epidemiol Biomarkers Prev. 2005;14:1567–70.CrossRefPubMedGoogle Scholar
  13. 13.
    Awad MR, El-Gamel A, Hasleton P, Turner DM, Sinnott PJ, Hutchinson IV. Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation. 1998;66:1014–20.CrossRefPubMedGoogle Scholar
  14. 14.
    Berndt SI, Huang WY, Chatterjee N, Yeager M, Welch R, Chanock SJ, et al. Transforming growth factor beta 1 (TGFB1) gene polymorphisms and risk of advanced colorectal adenoma. Carcinogenesis. 2007;28:1965–70.CrossRefPubMedGoogle Scholar
  15. 15.
    Stoll C, Mengsteab S, Stoll D, Riediger D, Gressner AM, Weiskirchen R. Analysis of polymorphic TGFB1 codons 10, 25, and 263 in a German patient group with non-syndromic cleft lip, alveolus, and palate compared with healthy adults. BMC Med Genet. 2004;5:15.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wei YS, Xu QQ, Wang CF, Pan Y, Liang F, Long XK. Genetic variation in transforming growth factor-beta1 gene associated with increased risk of esophageal squamous cell carcinoma. Tissue Antigens. 2007;70:464–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Zhang P, Di JZ, Zhu ZZ, Wu HM, Wang Y, Zhu G, et al. Association of transforming growth factor-beta 1 polymorphisms with genetic susceptibility to TNM stage I or II gastric cancer. Jpn J Clin Oncol. 2008;38:861–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Amani D, Dehaghani AS, Zolghadri J, Ravangard F, Niikawa N, Yoshiura K, et al. Lack of association between the TGF-beta1 gene polymorphisms and recurrent spontaneous abortion. J Reprod Immunol. 2005;68:91–103.CrossRefPubMedGoogle Scholar
  19. 19.
    Amani D, Zolghadri J, Dehaghani AS, Pezeshki AM, Ghaderi A. The promoter region (−800, −509) polymorphisms of transforming growth factor-beta1 (TGF-beta1) gene and recurrent spontaneous abortion. J Reprod Immunol. 2004;62:159–66.CrossRefPubMedGoogle Scholar
  20. 20.
    Derynck R, Rhee L, Chen EY, Van Tilburg A. Intron-exon structure of the human transforming growth factor-beta precursor gene. Nucleic Acids Res. 1987;15:3188–9.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Feizollahzadeh S, Taheripanah R, Khani M, Farokhi B, Amani D. Promoter region polymorphisms in the transforming growth factor beta-1 (TGFbeta1) gene and serum TGFbeta1 concentration in preeclamptic and control Iranian women. J Reprod Immunol. 2012;94:216–21.CrossRefPubMedGoogle Scholar
  22. 22.
    Skerrett DL, Moore EM, Bernstein DS, Vahdat L. Cytokine genotype polymorphisms in breast carcinoma: associations of TGF-beta1 with relapse. Cancer Investig. 2005;23:208–14.CrossRefGoogle Scholar
  23. 23.
    Ziv E, Cauley J, Morin PA, Saiz R, Browner WS. Association between the T29→C polymorphism in the transforming growth factor beta1 gene and breast cancer among elderly white women: The Study of Osteoporotic Fractures. JAMA. 2001;285:2859–63.CrossRefPubMedGoogle Scholar
  24. 24.
    Jin Q, Hemminki K, Grzybowska E, Klaes R, Soderberg M, Zientek H, et al. Polymorphisms and haplotype structures in genes for transforming growth factor beta1 and its receptors in familial and unselected breast cancers. Int J Cancer. 2004;112:94–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Le Marchand L, Haiman CA, van den Berg D, Wilkens LR, Kolonel LN, Henderson BE. T29C polymorphism in the transforming growth factor beta1 gene and postmenopausal breast cancer risk: the Multiethnic Cohort Study. Cancer Epidemiol Biomarkers Prev. 2004;13:412–5.PubMedGoogle Scholar
  26. 26.
    Lee KM, Park SK, Hamajima N, Tajima K, Yoo KY, Shin A, et al. Genetic polymorphisms of TGF-beta1 & TNF-beta and breast cancer risk. Breast Cancer Res Treat. 2005;90:149–55.CrossRefPubMedGoogle Scholar
  27. 27.
    Shu XO, Gao YT, Cai Q, Pierce L, Cai H, Ruan ZX, et al. Genetic polymorphisms in the TGF-beta 1 gene and breast cancer survival: a report from the Shanghai Breast Cancer Study. Cancer Res. 2004;64:836–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Cox DG, Penney K, Guo Q, Hankinson SE, Hunter DJ. TGFB1 and TGFBR1 polymorphisms and breast cancer risk in the Nurses’ Health Study. BMC Cancer. 2007;7:175.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Kaklamani VG, Baddi L, Liu J, Rosman D, Phukan S, Bradley C, et al. Combined genetic assessment of transforming growth factor-beta signaling pathway variants may predict breast cancer risk. Cancer Res. 2005;65:3454–61.PubMedGoogle Scholar
  30. 30.
    Krippl P, Langsenlehner U, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, et al. The L10P polymorphism of the transforming growth factor-beta 1 gene is not associated with breast cancer risk. Cancer Lett. 2003;201:181–4.CrossRefPubMedGoogle Scholar
  31. 31.
    Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, Reed MW, Pooley KA, et al. A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet. 2007;39:352–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Hishida A, Iwata H, Hamajima N, Matsuo K, Mizutani M, Iwase T, et al. Transforming growth factor B1 T29C polymorphism and breast cancer risk in Japanese women. Breast Cancer. 2003;10:63–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Ma X, Chen C, Xiong H, Li Y. Transforming growth factorbeta1 L10P variant plays an active role on the breast cancer susceptibility in Caucasian: evidence from 10,392 cases and 11,697 controls. Breast Cancer Res Treat. 2010;124:453–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Scollen S, Luccarini C, Baynes C, Driver K, Humphreys MK, Garcia-Closas M, et al. TGF-beta signaling pathway and breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev. 2011;20:1112–9.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Mu L, Katsaros D, Lu L, Preti M, Durando A, Arisio R, et al. TGF-beta1 genotype and phenotype in breast cancer and their associations with IGFs and patient survival. Br J Cancer. 2008;99:1357–63.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Breast Cancer Association C. Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium. J Natl Cancer Inst. 2006;98:1382–96.CrossRefGoogle Scholar
  37. 37.
    Amani D, Farjadian S, Ghaderi A. The frequency of transforming growth factor-beta1 gene polymorphisms in a normal southern Iranian population. Int J Immunogenet. 2008;35:145–51.CrossRefPubMedGoogle Scholar
  38. 38.
    Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Liu K, Muse SV. PowerMarker: an integrated analysis environment for genetic marker analysis. Bioinformatics. 2005;21:2128–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Vuong MT, Lundberg S, Gunnarsson I, Wramner L, Seddighzadeh M, Hahn-Zoric M, et al. Genetic variation in the transforming growth factor-beta1 gene is associated with susceptibility to IgA nephropathy. Nephrol Dial Transplant. 2009;24:3061–7.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Yokota M, Ichihara S, Lin TL, Nakashima N, Yamada Y. Association of a T29→C polymorphism of the transforming growth factor-beta1 gene with genetic susceptibility to myocardial infarction in Japanese. Circulation. 2000;101:2783–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Beisner J, Buck MB, Fritz P, Dippon J, Schwab M, Brauch H, et al. A novel functional polymorphism in the transforming growth factor-beta2 gene promoter and tumor progression in breast cancer. Cancer Res. 2006;66:7554–61.CrossRefPubMedGoogle Scholar
  43. 43.
    Ma X, Beeghly-Fadiel A, Lu W, Shi J, Xiang YB, Cai Q, et al. Pathway analyses identify TGFBR2 as potential breast cancer susceptibility gene: results from a consortium study among Asians. Cancer Epidemiol Biomarkers Prev. 2012;21:1176–84.CrossRefPubMedGoogle Scholar
  44. 44.
    Yamada Y, Miyauchi A, Goto J, Takagi Y, Okuizumi H, Kanematsu M, et al. Association of a polymorphism of the transforming growth factor-beta1 gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women. J Bone Miner Res. 1998;13:1569–76.CrossRefPubMedGoogle Scholar
  45. 45.
    Pelletier R, Pravica V, Perrey C, Xia D, Ferguson RM, Hutchinson I, et al. Evidence for a genetic predisposition towards acute rejection after kidney and simultaneous kidney-pancreas transplantation. Transplantation. 2000;70:674–80.CrossRefPubMedGoogle Scholar
  46. 46.
    Gewaltig J, Mangasser-Stephan K, Gartung C, Biesterfeld S, Gressner AM. Association of polymorphisms of the transforming growth factor-beta1 gene with the rate of progression of HCV-induced liver fibrosis. Clin Chim Acta. 2002;316:83–94.CrossRefPubMedGoogle Scholar
  47. 47.
    Feigelson HS, Patel AV, Diver WR, Stevens VL, Thun MJ, Calle EE. Transforming growth factor beta receptor type I and transforming growth factor beta1 polymorphisms are not associated with postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev. 2006;15:1236–7.CrossRefPubMedGoogle Scholar
  48. 48.
    Barnett GC, Coles CE, Burnet NG, Pharoah PD, Wilkinson J, West CM, et al. No association between SNPs regulating TGF-beta1 secretion and late radiotherapy toxicity to the breast: results from the RAPPER study. Radiother Oncol. 2010;97:9–14.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Band AM, Laiho M. Crosstalk of TGF-beta and estrogen receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia. 2011;16:109–15.CrossRefPubMedGoogle Scholar
  50. 50.
    Joshi NN, Kale MD, Hake SS, Kannan S. Transforming growth factor beta signaling pathway associated gene polymorphisms may explain lower breast cancer risk in western Indian women. PLoS One. 2011;6:e21866.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Langdahl BL, Uitterlinden AG, Ralston SH, Trikalinos TA, Balcells S, Brandi ML, et al. Large-scale analysis of association between polymorphisms in the transforming growth factor beta 1 gene (TGFB1) and osteoporosis: the GENOMOS study. Bone. 2008;42:969–81.CrossRefPubMedGoogle Scholar
  52. 52.
    Keen RW, Snieder H, Molloy H, Daniels J, Chiano M, Gibson F, et al. Evidence of association and linkage disequilibrium between a novel polymorphism in the transforming growth factor beta 1 gene and hip bone mineral density: a study of female twins. Rheumatology (Oxford). 2001;40:48–54.CrossRefGoogle Scholar
  53. 53.
    Langdahl BL, Carstens M, Stenkjaer L, Eriksen EF. Polymorphisms in the transforming growth factor beta 1 gene and osteoporosis. Bone. 2003;32:297–310.CrossRefPubMedGoogle Scholar
  54. 54.
    Bertoldo F, D’Agruma L, Furlan F, Colapietro F, Lorenzi MT, Maiorano N, et al. Transforming growth factor-beta1 gene polymorphism, bone turnover, and bone mass in Italian postmenopausal women. J Bone Miner Res. 2000;15:634–9.CrossRefPubMedGoogle Scholar
  55. 55.
    Weinshenker BG, Hebrink D, Kantarci OH, Schaefer-Klein J, Atkinson E, Schaid D, et al. Genetic variation in the transforming growth factor beta1 gene in multiple sclerosis. J Neuroimmunol. 2001;120:138–45.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Davar Amani
    • 1
  • Ahad Khalilnezhad
    • 1
  • Abbas Ghaderi
    • 2
    • 3
  • Norrio Niikawa
    • 4
  • Ko-ichiro Yoshiura
    • 4
  1. 1.Department of Immunology, Medical SchoolShahid Beheshti University of Medical SciencesTehranIran
  2. 2.Department of Immunology, Medical SchoolShiraz University of Medical SciencesShirazIran
  3. 3.Shiraz Institute of Cancer Research, Medical SchoolShiraz University of Medical SciencesShirazIran
  4. 4.Department of Human GeneticsNagasaki University Graduate School of Biomedical SciencesSakamotoJapan

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