Advertisement

Breast Cancer Research and Treatment

, Volume 178, Issue 1, pp 207–219 | Cite as

Transforming growth factor beta receptor II (TGFBR2) promoter region polymorphism in Brazilian breast cancer patients: association with susceptibility, clinicopathological features, and interaction with TGFB1 haplotypes

  • Glauco Akelinghton Freire Vitiello
  • Marla Karine Amarante
  • Bruna Karina Banin-Hirata
  • Clodoaldo Zago Campos
  • Karen Brajão de Oliveira
  • Roberta Losi-Guembarovski
  • Maria Angelica Ehara WatanabeEmail author
Epidemiology

Abstract

Purpose

Transforming growth factor beta (TGFβ) has paradoxical effects in breast cancer (BC), inhibiting initial tumors while promoting aggressive ones. A polymorphism on TGFBR2 promoter region (G-875A, rs3087465) increases TGFβ type II receptor expression and is protective against cancer. Previously, we have shown that TGFB1 variants have subtype-specific roles in BC. This work sought to investigate the association between TGFBR2 and susceptibility and clinicopathological features in BC subgroups.

Methods

TGFBR2 G-875A was analyzed through PCR-RFLP in 388 BC patients and 405 neoplasia-free women. Case–control analyses as well as interaction with TGFB1 haplotypes previously associated with BC were tested through age-adjusted logistic regression. Correlations between G-875A and clinicopathological parameters were assessed through Kendall’s Tau-b test. All statistical tests were two-tailed (α = 0.05).

Results

TGFBR2 G-875A was protective against BC in additive, genotypic, and dominant models. In subgroup-stratified analyses, these effects were greater in hormonal receptor-positive and luminal-A tumors, but were not significant in other subgroups. Logistic models including TGFB1 variants showed that in luminal-A tumors, G-875A retained its significance while TGFB1 haplotype showed a trend towards significance; otherwise, in HER2+ tumors TGFB1 variants remained significant while TGFBR2 showed a trend for association. There was no interaction between these genes. In correlation analyses, G-875A positively correlated with histopathological grade in total sample, and a trend towards significance was observed in triple-negative BCs.

Conclusion

These results indicate that G-875A is a protective factor against BC, especially from luminal-A subtype, but may promote anaplasia in established tumors, consistent with TGFβ signaling roles in BC.

Keywords

Transforming growth factor beta TGFBR2 Polymorphism Breast neoplasm Disease susceptibility 

Notes

Acknowledgements

The authors acknowledge all the volunteer donors involved in this study and the Clinical Hospital (HC-UEL) and Londrina Cancer Hospital (HCL) staff for supporting during sample collection.

Funding

This study was supported by the Brazilian National Council for Scientific and Technological Development (CNPq, process 303186/2015-1), Fundação Araucária (1027/2013), and by the Londrina State University Postgraduate Coordination (PROPPG-UEL).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Ethics Committee for Research Involving Human Subjects from Londrina State University - CEP/UEL 189/2013—CAAE 17123113400005231) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10549_2019_5370_MOESM1_ESM.docx (199 kb)
Supplementary material 1 (DOCX 199 kb)

References

  1. 1.
    Kubiczkova L, Sedlarikova L, Hajek R, Sevcikova S (2012) TGF-beta—an excellent servant but a bad master. J Transl Med 10:183.  https://doi.org/10.1186/1479-5876-10-183 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Vander Ark A, Cao J, Li X (2018) TGF-β receptors: in and beyond TGF-β signaling. Cell Signal 52:112–120.  https://doi.org/10.1016/j.cellsig.2018.09.002 CrossRefPubMedGoogle Scholar
  3. 3.
    Bierie B, Moses HL (2010) Transforming growth factor beta (TGF-beta) and inflammation in cancer. Cytokine Growth Factor Rev 21(1):49–59.  https://doi.org/10.1016/j.cytogfr.2009.11.008 CrossRefPubMedGoogle Scholar
  4. 4.
    Yang L, Pang Y, Moses HL (2010) TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol 31(6):220–227.  https://doi.org/10.1016/j.it.2010.04.002 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tang B, Vu M, Booker T, Santner SJ, Miller FR, Anver MR, Wakefield LM (2003) TGF-β switches from tumor suppressor to prometastatic factor in a model of breast cancer progression. J Clin Investig 112(7):1116–1124.  https://doi.org/10.1172/jci200318899 CrossRefPubMedGoogle Scholar
  6. 6.
    Bierie B, Moses HL (2014) Gain or loss of TGF-β signaling in mammary carcinoma cells can promote metastasis. Cell Cycle 8(20):3319–3327.  https://doi.org/10.4161/cc.8.20.9727 CrossRefGoogle Scholar
  7. 7.
    Parvani JG, Taylor MA, Schiemann WP (2011) Noncanonical TGF-beta signaling during mammary tumorigenesis. J Mammary Gland Biol Neoplas 16(2):127–146.  https://doi.org/10.1007/s10911-011-9207-3 CrossRefGoogle Scholar
  8. 8.
    Wilson CA, Cajulis EE, Green JL, Olsen TM, Chung Y, Damore MA, Dering J, Calzone FJ, Slamon DJ (2005) HER-2 overexpression differentially alters transforming growth factor-β responses in luminal versus mesenchymal human breast cancer cells. Breast Cancer Res 7(6):R1058.  https://doi.org/10.1186/bcr1343 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Vitiello GAF, Guembarovski RL, Hirata BKB, Amarante MK, de Oliveira CEC, de Oliveira KB, Cebinelli GCM, Guembarovski AL, Campos CZ, Watanabe MAE (2018) Transforming growth factor beta 1 (TGFβ1) polymorphisms and haplotype structures have dual roles in breast cancer pathogenesis. J Cancer Res Clin Oncol 144(4):645–655.  https://doi.org/10.1007/s00432-018-2585-9 CrossRefPubMedGoogle Scholar
  10. 10.
    Seijo ER, Song H, Lynch MA, Jennings R, Qong X, Lazaridis E, Muro-Cacho C, Weghorst CM, Muñoz-Antonia T (2001) Identification of genetic alterations in the TGFβ type II receptor gene promoter. Mutat Res 483(1–2):19–26.  https://doi.org/10.1016/s0027-5107(01)00217-2 CrossRefPubMedGoogle Scholar
  11. 11.
    Teixeira AL, Gomes M, Nogueira A, Azevedo AS, Assis J, Dias F, Santos JI, Lobo F, Morais A, Mauricio J, Medeiros R (2013) Improvement of a predictive model of castration-resistant prostate cancer: functional genetic variants in TGFbeta1 signaling pathway modulation. PLoS ONE 8(8):e72419.  https://doi.org/10.1371/journal.pone.0072419 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Ren Y, Yin Z, Li K, Wan Y, Li X, Wu W, Guan P, Zhou B (2015) TGFβ-1 and TGFBR2 polymorphisms, cooking oil fume exposure and risk of lung adenocarcinoma in Chinese nonsmoking females: a case control study. BMC Med Genet.  https://doi.org/10.1186/s12881-015-0170-5 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Jin G, Wang L, Chen W, Hu Z, Zhou Y, Tan Y, Wang J, Hua Z, Ding W, Shen J, Zhang Z, Wang X, Xu Y, Shen H (2007) Variant alleles ofTGFB1 andTGFBR2 are associated with a decreased risk of gastric cancer in a Chinese population. Int J Cancer 120(6):1330–1335.  https://doi.org/10.1002/ijc.22443 CrossRefPubMedGoogle Scholar
  14. 14.
    Xu L, Zeng Z, Chen BIN, Wu X, Yu JUN, Xue L, Tian L, Wang Y, Chen M, Sung JJY, Hu P (2011) Association between the TGFB1 -509C/T and TGFBR2 -875A/G polymorphisms and gastric cancer: a case-control study. Oncol Lett 2(2):371–377.  https://doi.org/10.3892/ol.2011.249 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Jin G, Deng Y, Miao R, Hu Z, Zhou Y, Tan Y, Wang J, Hua Z, Ding W, Wang L, Chen W, Shen J, Wang X, Xu Y, Shen H (2007) TGFB1 and TGFBR2 functional polymorphisms and risk of esophageal squamous cell carcinoma: a case–control analysis in a Chinese population. J Cancer Res Clin Oncol 134(3):345–351.  https://doi.org/10.1007/s00432-007-0290-1 CrossRefPubMedGoogle Scholar
  16. 16.
    Zhang MEI, Guo L-L, Cheng Z, Liu R-Y, Lu Y, Qian Q, Lei ZHE, Zhang H-T (2011) A functional polymorphism of TGFBR2 is associated with risk of breast cancer with ER + , PR + , ER + PR + and HER2 − expression in women. Oncol Lett 2(4):653–658.  https://doi.org/10.3892/ol.2011.312 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Jin Q, Hemminki K, Grzybowska E, Klaes R, Söderberg M, Zientek H, Rogozinska-Szczepka J, Utracka-Hutka B, Pamula J, Pekala W, Försti A (2004) Polymorphisms and haplotype structures in genes for transforming growth factorβ1 and its receptors in familial and unselected breast cancers. Int J Cancer 112(1):94–99.  https://doi.org/10.1002/ijc.20370 CrossRefPubMedGoogle Scholar
  18. 18.
    Huang Y-S, Zhong Y, Yu L, Wang L (2014) Association between the TGFBR2 G-875A Polymorphism and Cancer Risk: evidence from a Meta-analysis. Asian Pac J Cancer Prev 15(20):8705–8708.  https://doi.org/10.7314/apjcp.2014.15.20.8705 CrossRefPubMedGoogle Scholar
  19. 19.
    Vitiello GAF, Losi Guembarovski R, Amarante MK, Ceribelli JR, Carmelo ECB, Watanabe MAE (2018) Interleukin 7 receptor alpha Thr244Ile genetic polymorphism is associated with susceptibility and prognostic markers in breast cancer subgroups. Cytokine 103:121–126.  https://doi.org/10.1016/j.cyto.2017.09.019 CrossRefPubMedGoogle Scholar
  20. 20.
    Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JMS, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31(31):3997–4013.  https://doi.org/10.1200/jco.2013.50.9984 CrossRefPubMedGoogle Scholar
  21. 21.
    Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC, American Society of Clinical O, College of American P (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med 134(7):e48–e72.  https://doi.org/10.1043/1543-2165-134.7.e48 CrossRefPubMedGoogle Scholar
  22. 22.
    Naslavsky MS, Yamamoto GL, de Almeida TF, Ezquina SAM, Sunaga DY, Pho N, Bozoklian D, Sandberg TOM, Brito LA, Lazar M, Bernardo DV, Amaro E, Duarte YAO, Lebrão ML, Passos-Bueno MR, Zatz M (2017) Exomic variants of an elderly cohort of Brazilians in the ABraOM database. Hum Mutat 38(7):751–763.  https://doi.org/10.1002/humu.23220 CrossRefPubMedGoogle Scholar
  23. 23.
    Pena SD, Bastos-Rodrigues L, Pimenta JR, Bydlowski SP (2009) DNA tests probe the genomic ancestry of Brazilians. Braz J Med Biol Res 42(10):870–876CrossRefGoogle Scholar
  24. 24.
    Pimenta JR, Zuccherato LW, Debes AA, Maselli L, Soares RP, Moura-Neto RS, Rocha J, Bydlowski SP, Pena SD (2006) Color and genomic ancestry in Brazilians: a study with forensic microsatellites. Hum Hered 62(4):190–195.  https://doi.org/10.1159/000096872 CrossRefPubMedGoogle Scholar
  25. 25.
    Kehdy FS, Gouveia MH, Machado M, Magalhaes WC, Horimoto AR, Horta BL, Moreira RG, Leal TP, Scliar MO, Soares-Souza GB, Rodrigues-Soares F, Araujo GS, Zamudio R, Sant Anna HP, Santos HC, Duarte NE, Fiaccone RL, Figueiredo CA, Silva TM, Costa GN, Beleza S, Berg DE, Cabrera L, Debortoli G, Duarte D, Ghirotto S, Gilman RH, Goncalves VF, Marrero AR, Muniz YC, Weissensteiner H, Yeager M, Rodrigues LC, Barreto ML, Lima-Costa MF, Pereira AC, Rodrigues MR, Tarazona-Santos E, Brazilian EPC (2015) Origin and dynamics of admixture in Brazilians and its effect on the pattern of deleterious mutations. Proc Natl Acad Sci USA 112(28):8696–8701.  https://doi.org/10.1073/pnas.1504447112 CrossRefPubMedGoogle Scholar
  26. 26.
    Lins TC, Vieira RG, Abreu BS, Grattapaglia D, Pereira RW (2009) Genetic composition of Brazilian population samples based on a set of twenty-eight ancestry informative SNPs. Am J Hum Biol.  https://doi.org/10.1002/ajhb.20976 CrossRefGoogle Scholar
  27. 27.
    Parra FC, Amado RC, Lambertucci JR, Rocha J, Antunes CM, Pena SD (2003) Color and genomic ancestry in Brazilians. Proc Natl Acad Sci USA 100(1):177–182.  https://doi.org/10.1073/pnas.0126614100 CrossRefPubMedGoogle Scholar
  28. 28.
    Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215CrossRefGoogle Scholar
  29. 29.
    Isola J, DeVries S, Chu L, Ghazvini S, Waldman F (1994) Analysis of changes in DNA sequence copy number by comparative genomic hybridization in archival paraffin-embedded tumor samples. Am J Pathol 145(6):1301–1308PubMedPubMedCentralGoogle Scholar
  30. 30.
    Adorno M, Cordenonsi M, Montagner M, Dupont S, Wong C, Hann B, Solari A, Bobisse S, Rondina MB, Guzzardo V, Parenti AR, Rosato A, Bicciato S, Balmain A, Piccolo S (2009) A mutant-p53/Smad complex opposes p63 to empower TGFβ-induced metastasis. Cell 137(1):87–98.  https://doi.org/10.1016/j.cell.2009.01.039 CrossRefPubMedGoogle Scholar
  31. 31.
    Wang SE (2011) The functional crosstalk between HER2 tyrosine kinase and TGF-β signaling in breast cancer malignancy. J Signal Transduct 2011:1–8.  https://doi.org/10.1155/2011/804236 CrossRefGoogle Scholar
  32. 32.
    Shin A (2005) Genetic polymorphisms of the transforming growth factor- 1 gene and breast cancer risk: a possible dual role at different cancer stages. Cancer Epidemiol Biomark Prev 14(6):1567–1570.  https://doi.org/10.1158/1055-9965.epi-05-0078 CrossRefGoogle Scholar
  33. 33.
    Levy L, Hill C (2006) Alterations in components of the TGF-β superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev 17(1–2):41–58.  https://doi.org/10.1016/j.cytogfr.2005.09.009 CrossRefPubMedGoogle Scholar
  34. 34.
    Kim SJ, Im YH, Markowitz SD, Bang YJ (2000) Molecular mechanisms of inactivation of TGF-beta receptors during carcinogenesis. Cytokine Growth Factor Rev 11(1–2):159–168CrossRefGoogle Scholar
  35. 35.
    Lucke CD, Philpott A, Metcalfe JC, Thompson AM, Hughes-Davies L, Kemp PR, Hesketh R (2001) Inhibiting mutations in the transforming growth factor beta type 2 receptor in recurrent human breast cancer. Cancer Res 61(2):482–485PubMedGoogle Scholar
  36. 36.
    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data: figure 1. Cancer Discov 2(5):401–404.  https://doi.org/10.1158/2159-8290.cd-12-0095 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):l1–21.  https://doi.org/10.1126/scisignal.2004088 CrossRefGoogle Scholar
  38. 38.
    Asiedu MK, Ingle JN, Behrens MD, Radisky DC, Knutson KL (2011) TGF/TNF -mediated epithelial-mesenchymal transition generates breast cancer stem cells with a claudin-low phenotype. Cancer Res 71(13):4707–4719.  https://doi.org/10.1158/0008-5472.can-10-4554 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Bierie B, Chung CH, Parker JS, Stover DG, Cheng N, Chytil A, Aakre M, Shyr Y, Moses HL (2009) Abrogation of TGF-β signaling enhances chemokine production and correlates with prognosis in human breast cancer. J Clin Investig 119(6):1571–1582.  https://doi.org/10.1172/jci37480 CrossRefPubMedGoogle Scholar
  40. 40.
    Oda JMM, de Oliveira KB, Guembarovski RL, de Lima KWA, do Amaral ACDS, Guembarovski AL, Sobrinho WJ, Derossi DR, Watanabe MAE (2012) TGF-β polymorphism and its expression correlated with CXCR20 expression in human breast cancer. Mol Biol Rep 39(12):10131–10137.  https://doi.org/10.1007/s11033-012-1887-2 CrossRefPubMedGoogle Scholar
  41. 41.
    Pang MF, Georgoudaki AM, Lambut L, Johansson J, Tabor V, Hagikura K, Jin Y, Jansson M, Alexander JS, Nelson CM, Jakobsson L, Betsholtz C, Sund M, Karlsson MC, Fuxe J (2015) TGF-beta1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR1/CCL21-mediated chemotaxis. Oncogene.  https://doi.org/10.1038/onc.2015.133 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Forrester E, Chytil A, Bierie B, Aakre M, Gorska AE, Sharif-Afshar A-R, Muller WJ, Moses HL (2005) Effect of conditional knockout of the type IITGF-βreceptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis. Cancer Res 65(6):2296–2302.  https://doi.org/10.1158/0008-5472.can-04-3272 CrossRefPubMedGoogle Scholar
  43. 43.
    Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, Carbone DP, Matrisian Lynn M, Richmond A, Lin PC, Moses HL (2008) Abrogation of TGFβ signaling in mammary carcinomas recruits Gr-1 + CD11b + myeloid cells that promote metastasis. Cancer Cell 13(1):23–35.  https://doi.org/10.1016/j.ccr.2007.12.004 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Padua D, Zhang XHF, Wang Q, Nadal C, Gerald WL, Gomis RR, Massagué J (2008) TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133(1):66–77.  https://doi.org/10.1016/j.cell.2008.01.046 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Grabe N (2002) AliBaba2: context specific identification of transcription factor binding sites. Silico Biol 2(1):S1–15Google Scholar
  46. 46.
    Choe B-K, Kim SK, Park HJ, Park H-K, Kwon KH, Lim SH, Yim S-V (2012) Polymorphisms of TGFBR2 contribute to the progression of papillary thyroid carcinoma. Mol Cell Toxicol 8(1):1–8.  https://doi.org/10.1007/s13273-012-0001-0 CrossRefGoogle Scholar
  47. 47.
    Messeguer X, Escudero R, Farre D, Nunez O, Martinez J, Alba MM (2002) PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics 18(2):333–334.  https://doi.org/10.1093/bioinformatics/18.2.333 CrossRefPubMedGoogle Scholar
  48. 48.
    ENCODE Project Consortium (2004) The ENCODE (ENCyclopedia Of DNA Elements) Project. Science 306(5696):636–640.  https://doi.org/10.1126/science.1105136 CrossRefGoogle Scholar
  49. 49.
    Ward LD, Kellis M (2011) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40(D1):D930–D934.  https://doi.org/10.1093/nar/gkr917 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Cleator S, Heller W, Coombes RC (2007) Triple-negative breast cancer: therapeutic options. Lancet Oncol 8(3):235–244.  https://doi.org/10.1016/s1470-2045(07)70074-8 CrossRefGoogle Scholar
  51. 51.
    Sato M, Kadota M, Tang B, Yang HH, Yang Y-a, Shan M, Weng J, Welsh MA, Flanders KC, Nagano Y, Michalowski AM, Clifford RJ, Lee MP, Wakefield LM (2014) An integrated genomic approach identifies persistent tumor suppressive effects of transforming growth factor-β in human breast cancer. Breast Cancer Res.  https://doi.org/10.1186/bcr3668 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Gibbs RA, Boerwinkle E, Doddapaneni H, Han Y, Korchina V, Kovar C, Lee S, Muzny D, Reid JG, Zhu Y, Wang J, Chang Y, Feng Q, Fang X, Guo X, Jian M, Jiang H, Jin X, Lan T, Li G, Li J, Li Y, Liu S, Liu X, Lu Y, Ma X, Tang M, Wang B, Wang G, Wu H, Wu R, Xu X, Yin Y, Zhang D, Zhang W, Zhao J, Zhao M, Zheng X, Lander ES, Altshuler DM, Gabriel SB, Gupta N, Gharani N, Toji LH, Gerry NP, Resch AM, Flicek P, Barker J, Clarke L, Gil L, Hunt SE, Kelman G, Kulesha E, Leinonen R, McLaren WM, Radhakrishnan R, Roa A, Smirnov D, Smith RE, Streeter I, Thormann A, Toneva I, Vaughan B, Zheng-Bradley X, Bentley DR, Grocock R, Humphray S, James T, Kingsbury Z, Lehrach H, Sudbrak R, Albrecht MW, Amstislavskiy VS, Borodina TA, Lienhard M, Mertes F, Sultan M, Timmermann B, Yaspo M-L, Mardis ER, Wilson RK, Fulton L, Fulton R, Sherry ST, Ananiev V, Belaia Z, Beloslyudtsev D, Bouk N, Chen C, Church D, Cohen R, Cook C, Garner J, Hefferon T, Kimelman M, Liu C, Lopez J, Meric P, O’Sullivan C, Ostapchuk Y, Phan L, Ponomarov S, Schneider V, Shekhtman E, Sirotkin K, Slotta D, Zhang H, McVean GA, Durbin RM, Balasubramaniam S, Burton J, Danecek P, Keane TM, Kolb-Kokocinski A, McCarthy S, Stalker J, Quail M, Schmidt JP, Davies CJ, Gollub J, Webster T, Wong B, Zhan Y, Auton A, Campbell CL, Kong Y, Marcketta A, Gibbs RA, Yu F, Antunes L, Bainbridge M, Muzny D, Sabo A, Huang Z, Wang J, Coin LJM, Fang L, Guo X, Jin X, Li G, Li Q, Li Y, Li Z, Lin H, Liu B, Luo R, Shao H, Xie Y, Ye C, Yu C, Zhang F, Zheng H, Zhu H, Alkan C, Dal E, Kahveci F, Marth GT, Garrison EP, Kural D, Lee W-P, Fung Leong W, Stromberg M, Ward AN, Wu J, Zhang M, Daly MJ, DePristo MA, Handsaker RE, Altshuler DM, Banks E, Bhatia G, del Angel G, Gabriel SB, Genovese G, Gupta N, Li H, Kashin S, Lander ES, McCarroll SA, Nemesh JC, Poplin RE, Yoon SC, Lihm J, Makarov V, Clark AG, Gottipati S, Keinan A, Rodriguez-Flores JL, Korbel JO, Rausch T, Fritz MH, Stütz AM, Flicek P, Beal K, Clarke L, Datta A, Herrero J, McLaren WM, Ritchie GRS, Smith RE, Zerbino D, Zheng-Bradley X, Sabeti PC, Shlyakhter I, Schaffner SF, Vitti J, Cooper DN, Ball EV, Stenson PD, Bentley DR, Barnes B, Bauer M, Keira Cheetham R, Cox A, Eberle M, Humphray S, Kahn S, Murray L, Peden J, Shaw R, Kenny EE, Batzer MA, Konkel MK, Walker JA, MacArthur DG, Lek M, Sudbrak R, Amstislavskiy VS, Herwig R, Mardis ER, Ding L, Koboldt DC, Larson D, Ye K, Gravel S, Swaroop A, Chew E, Lappalainen T, Erlich Y, Gymrek M, Frederick Willems T, Simpson JT, Shriver MD, Rosenfeld JA, Bustamante CD, Montgomery SB, De La Vega FM, Byrnes JK, Carroll AW, DeGorter MK, Lacroute P, Maples BK, Martin AR, Moreno-Estrada A, Shringarpure SS, Zakharia F, Halperin E, Baran Y, Lee C, Cerveira E, Hwang J, Malhotra A, Plewczynski D, Radew K, Romanovitch M, Zhang C, Hyland FCL, Craig DW, Christoforides A, Homer N, Izatt T, Kurdoglu AA, Sinari SA, Squire K, Sherry ST, Xiao C, Sebat J, Antaki D, Gujral M, Noor A, Ye K, Burchard EG, Hernandez RD, Gignoux CR, Haussler D, Katzman SJ, James Kent W, Howie B, Ruiz-Linares A, Dermitzakis ET, Devine SE, Abecasis GR, Min Kang H, Kidd JM, Blackwell T, Caron S, Chen W, Emery S, Fritsche L, Fuchsberger C, Jun G, Li B, Lyons R, Scheller C, Sidore C, Song S, Sliwerska E, Taliun D, Tan A, Welch R, Kate Wing M, Zhan X, Awadalla P, Hodgkinson A, Li Y, Shi X, Quitadamo A, Lunter G, McVean GA, Marchini JL, Myers S, Churchhouse C, Delaneau O, Gupta-Hinch A, Kretzschmar W, Iqbal Z, Mathieson I, Menelaou A, Rimmer A, Xifara DK, Oleksyk TK, Fu Y, Liu X, Xiong M, Jorde L, Witherspoon D, Xing J, Eichler EE, Browning BL, Browning SR, Hormozdiari F, Sudmant PH, Khurana E, Durbin RM, Hurles ME, Tyler-Smith C, Albers CA, Ayub Q, Balasubramaniam S, Chen Y, Colonna V, Danecek P, Jostins L, Keane TM, McCarthy S, Walter K, Xue Y, Gerstein MB, Abyzov A, Balasubramanian S, Chen J, Clarke D, Fu Y, Harmanci AO, Jin M, Lee D, Liu J, Jasmine MuX, Zhang J, Zhang Y, Li Y, Luo R, Zhu H, Alkan C, Dal E, Kahveci F, Marth GT, Garrison EP, Kural D, Lee W-P, Ward AN, Wu J, Zhang M, McCarroll SA, Handsaker RE, Altshuler DM, Banks E, del Angel G, Genovese G, Hartl C, Li H, Kashin S, Nemesh JC, Shakir K, Yoon SC, Lihm J, Makarov V, Degenhardt J, Korbel JO, Fritz MH, Meiers S, Raeder B, Rausch T, Stütz AM, Flicek P, Paolo Casale F, Clarke L, Smith RE, Stegle O, Zheng-Bradley X, Bentley DR, Barnes B, Keira Cheetham R, Eberle M, Humphray S, Kahn S, Murray L, Shaw R, Lameijer E-W, Batzer MA, Konkel MK, Walker JA, Ding L, Hall I, Ye K, Lacroute P, Lee C, Cerveira E, Malhotra A, Hwang J, Plewczynski D, Radew K, Romanovitch M, Zhang C, Craig DW, Homer N, Church D, Xiao C, Sebat J, Antaki D, Bafna V, Michaelson J, Ye K, Devine SE, Gardner EJ, Abecasis GR, Kidd JM, Mills RE, Dayama G, Emery S, Jun G, Shi X, Quitadamo A, Lunter G, McVean GA, Chen K, Fan X, Chong Z, Chen T, Witherspoon D, Xing J, Eichler EE, Chaisson MJ, Hormozdiari F, Huddleston J, Malig M, Nelson BJ, Sudmant PH, Parrish NF, Khurana E, Hurles ME, Blackburne B, Lindsay SJ, Ning Z, Walter K, Zhang Y, Gerstein MB, Abyzov A, Chen J, Clarke D, Lam H, Jasmine MuX, Sisu C, Zhang J, Zhang Y, Gibbs RA, Yu F, Bainbridge M, Challis D, Evani US, Kovar C, Lu J, Muzny D, Nagaswamy U, Reid JG, Sabo A, Yu J, Guo X, Li W, Li Y, Wu R, Marth GT, Garrison EP, Fung Leong W, Ward AN, del Angel G, DePristo MA, Gabriel SB, Gupta N, Hartl C, Poplin RE, Clark AG, Rodriguez-Flores JL, Flicek P, Clarke L, Smith RE, Zheng-Bradley X, MacArthur DG, Mardis ER, Fulton R, Koboldt DC, Gravel S, Bustamante CD, Craig DW, Christoforides A, Homer N, Izatt T, Sherry ST, Xiao C, Dermitzakis ET, Abecasis GR, Min Kang H, McVean GA, Gerstein MB, Balasubramanian S, Habegger L, Yu H, Flicek P, Clarke L, Cunningham F, Dunham I, Zerbino D, Zheng-Bradley X, Lage K, Berg Jespersen J, Horn H, Montgomery SB, DeGorter MK, Khurana E, Tyler-Smith C, Chen Y, Colonna V, Xue Y, Gerstein MB, Balasubramanian S, Fu Y, Kim D, Auton A, Marcketta A, Desalle R, Narechania A, Wilson Sayres MA, Garrison EP, Handsaker RE, Kashin S, McCarroll SA, Rodriguez-Flores JL, Flicek P, Clarke L, Zheng-Bradley X, Erlich Y, Gymrek M, Frederick Willems T, Bustamante CD, Mendez FL, David Poznik G, Underhill PA, Lee C, Cerveira E, Malhotra A, Romanovitch M, Zhang C, Abecasis GR, Coin L, Shao H, Mittelman D, Tyler-Smith C, Ayub Q, Banerjee R, Cerezo M, Chen Y, Fitzgerald TW, Louzada S, Massaia A, McCarthy S, Ritchie GR, Xue Y, Yang F, Gibbs RA, Kovar C, Kalra D, Hale W, Muzny D, Reid JG, Wang J, Dan X, Guo X, Li G, Li Y, Ye C, Zheng X, Altshuler DM, Flicek P, Clarke L, Zheng-Bradley X, Bentley DR, Cox A, Humphray S, Kahn S, Sudbrak R, Albrecht MW, Lienhard M, Larson D, Craig DW, Izatt T, Kurdoglu AA, Sherry ST, Xiao C, Haussler D, Abecasis GR, McVean GA, Durbin RM, Balasubramaniam S, Keane TM, McCarthy S, Stalker J, Bodmer W, Bedoya G, Ruiz-Linares A, Cai Z, Gao Y, Chu J, Peltonen L, Garcia-Montero A, Orfao A, Dutil J, Martinez-Cruzado JC, Oleksyk TK, Barnes KC, Mathias RA, Hennis A, Watson H, McKenzie C, Qadri F, LaRocque R, Sabeti PC, Zhu J, Deng X, Sabeti PC, Asogun D, Folarin O, Happi C, Omoniwa O, Stremlau M, Tariyal R, Jallow M, Sisay Joof F, Corrah T, Rockett K, Kwiatkowski D, Kooner J, Tịnh Hiê`n TN, Dunstan SJ, Thuy Hang N, Fonnie R, Garry R, Kanneh L, Moses L, Sabeti PC, Schieffelin J, Grant DS, Gallo C, Poletti G, Saleheen D, Rasheed A (2015) A global reference for human genetic variation. Nature 526(7571):68–74.  https://doi.org/10.1038/nature15393 CrossRefGoogle Scholar
  53. 53.
    Sudmant PH, Rausch T, Gardner EJ, Handsaker RE, Abyzov A, Huddleston J, Zhang Y, Ye K, Jun G, Hsi-Yang Fritz M, Konkel MK, Malhotra A, Stütz AM, Shi X, Paolo Casale F, Chen J, Hormozdiari F, Dayama G, Chen K, Malig M, Chaisson MJP, Walter K, Meiers S, Kashin S, Garrison E, Auton A, Lam HYK, Jasmine MuX, Alkan C, Antaki D, Bae T, Cerveira E, Chines P, Chong Z, Clarke L, Dal E, Ding L, Emery S, Fan X, Gujral M, Kahveci F, Kidd JM, Kong Y, Lameijer E-W, McCarthy S, Flicek P, Gibbs RA, Marth G, Mason CE, Menelaou A, Muzny DM, Nelson BJ, Noor A, Parrish NF, Pendleton M, Quitadamo A, Raeder B, Schadt EE, Romanovitch M, Schlattl A, Sebra R, Shabalin AA, Untergasser A, Walker JA, Wang M, Yu F, Zhang C, Zhang J, Zheng-Bradley X, Zhou W, Zichner T, Sebat J, Batzer MA, McCarroll SA, Mills RE, Gerstein MB, Bashir A, Stegle O, Devine SE, Lee C, Eichler EE, Korbel JO (2015) An integrated map of structural variation in 2504 human genomes. Nature 526(7571):75–81.  https://doi.org/10.1038/nature15394 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Machiela MJ, Chanock SJ (2015) LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants: fig. 1. Bioinformatics 31(21):3555–3557.  https://doi.org/10.1093/bioinformatics/btv402 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne RL, Schmidt MK, Chang-Claude J, Bojesen SE, Bolla MK, Wang Q, Dicks E, Lee A, Turnbull C, Rahman N, Fletcher O, Peto J, Gibson L, dos Santos Silva I, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Czene K, Irwanto A, Liu J, Waisfisz Q, Meijers-Heijboer H, Adank M, van der Luijt RB, Hein R, Dahmen N, Beckman L, Meindl A, Schmutzler RK, Müller-Myhsok B, Lichtner P, Hopper JL, Southey MC, Makalic E, Schmidt DF, Uitterlinden AG, Hofman A, Hunter DJ, Chanock SJ, Vincent D, Bacot F, Tessier DC, Canisius S, Wessels LFA, Haiman CA, Shah M, Luben R, Brown J, Luccarini C, Schoof N, Humphreys K, Li J, Nordestgaard BG, Nielsen SF, Flyger H, Couch FJ, Wang X, Vachon C, Stevens KN, Lambrechts D, Moisse M, Paridaens R, Christiaens M-R, Rudolph A, Nickels S, Flesch-Janys D, Johnson N, Aitken Z, Aaltonen K, Heikkinen T, Broeks A, Veer LJVT, van der Schoot CE, Guénel P, Truong T, Laurent-Puig P, Menegaux F, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Zamora MP, Perez JIA, Pita G, Alonso MR, Cox A, Brock IW, Cross SS, Reed MWR, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Henderson BE, Schumacher F, Le Marchand L, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Lindblom A, Margolin S, Hooning MJ, Hollestelle A, van den Ouweland AMW, Jager A, Bui QM, Stone J, Dite GS, Apicella C, Tsimiklis H, Giles GG, Severi G, Baglietto L, Fasching PA, Haeberle L, Ekici AB, Beckmann MW, Brenner H, Müller H, Arndt V, Stegmaier C, Swerdlow A, Ashworth A, Orr N, Jones M, Figueroa J, Lissowska J, Brinton L, Goldberg MS, Labrèche F, Dumont M, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Brauch H, Hamann U, Brüning T, Radice P, Peterlongo P, Manoukian S, Bonanni B, Devilee P, Tollenaar RAEM, Seynaeve C, van Asperen CJ, Jakubowska A, Lubinski J, Jaworska K, Durda K, Mannermaa A, Kataja V, Kosma V-M, Hartikainen JM, Bogdanova NV, Antonenkova NN, Dörk T, Kristensen VN, Anton-Culver H, Slager S, Toland AE, Edge S, Fostira F, Kang D, Yoo K-Y, Noh D-Y, Matsuo K, Ito H, Iwata H, Sueta A, Wu AH, Tseng C-C, Van Den Berg D, Stram DO, Shu X-O, Lu W, Gao Y-T, Cai H, Teo SH, Yip CH, Phuah SY, Cornes BK, Hartman M, Miao H, Lim WY, Sng J-H, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Shen C-Y, Hsiung C-N, Wu P-E, Ding S-L, Sangrajrang S, Gaborieau V, Brennan P, McKay J, Blot WJ, Signorello LB, Cai Q, Zheng W, Deming-Halverson S, Shrubsole M, Long J, Simard J, Garcia-Closas M, Pharoah PDP, Chenevix-Trench G, Dunning AM, Benitez J, Easton DF (2013) Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet 45(4):353–361.  https://doi.org/10.1038/ng.2563 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Zhang B, Li Y, Li L, Chen M, Zhang C, Zuo X-b, Zhou F-s, Liang B, Zhu J, Li P, Huang Z-l, Xuan H, Li W, Chen Z-d (2014) Association study of susceptibility loci with specific breast cancer subtypes in Chinese women. Breast Cancer Res Treat 146(3):503–514.  https://doi.org/10.1007/s10549-014-3041-4 CrossRefPubMedGoogle Scholar
  57. 57.
    Scollen S, Luccarini C, Baynes C, Driver K, Humphreys MK, Garcia-Closas M, Figueroa J, Lissowska J, Pharoah PD, Easton DF, Hesketh R, Metcalfe JC, Dunning AM (2011) TGF- signaling pathway and breast cancer susceptibility. Cancer Epidemiol Biomark Prev 20(6):1112–1119.  https://doi.org/10.1158/1055-9965.epi-11-0062 CrossRefGoogle Scholar
  58. 58.
    Ma X, Beeghly-Fadiel A, Lu W, Shi J, Xiang YB, Cai Q, Shen H, Shen CY, Ren Z, Matsuo K, Khoo US, Iwasaki M, Long J, Zhang B, Ji BT, Zheng Y, Wang W, Hu Z, Liu Y, Wu PE, Shieh YL, Wang S, Xie X, Ito H, Kasuga Y, Chan KYK, Iwata H, Tsugane S, Gao YT, Shu XO, Moses HL, Zheng W (2012) Pathway analyses identify TGFBR2 as potential breast cancer susceptibility gene: results from a consortium study among Asians. Cancer Epidemiol Biomark Prev 21(7):1176–1184.  https://doi.org/10.1158/1055-9965.epi-12-0118 CrossRefGoogle Scholar
  59. 59.
    Chow A, Arteaga CL, Wang SE (2011) When tumor suppressor TGFβ meets the HER2 (ERBB2) oncogene. J Mammary Gland Biol Neoplas 16(2):81–88.  https://doi.org/10.1007/s10911-011-9206-4 CrossRefGoogle Scholar
  60. 60.
    Buck MB, Fritz P, Dippon J, Zugmaier G, Knabbe C (2004) Prognostic significance of transforming growth factor beta receptor II in estrogen receptor-negative breast cancer patients. Clin Cancer Res 10(2):491–498CrossRefGoogle Scholar
  61. 61.
    Busch S, Sims AH, Stal O, Ferno M, Landberg G (2015) Loss of TGFbeta receptor type 2 expression impairs estrogen response and confers tamoxifen resistance. Cancer Res 75(7):1457–1469.  https://doi.org/10.1158/0008-5472.CAN-14-1583 CrossRefPubMedGoogle Scholar
  62. 62.
    Lei J, Rudolph A, Moysich KB, Rafiq S, Behrens S, Goode EL, Pharoah PPD, Seibold P, Fasching PA, Andrulis IL, Kristensen VN, Couch FJ, Hamann U, Hooning MJ, Nevanlinna H, Eilber U, Bolla MK, Dennis J, Wang Q, Lindblom A, Mannermaa A, Lambrechts D, García-Closas M, Hall P, Chenevix-Trench G, Shah M, Luben R, Haeberle L, Ekici AB, Beckmann MW, Knight JA, Glendon G, Tchatchou S, Alnæs GIG, Borresen-Dale A-L, Nord S, Olson JE, Hallberg E, Vachon C, Torres D, Ulmer H-U, Rüdiger T, Jager A, van Deurzen CHM, Tilanus-Linthorst MMA, Muranen TA, Aittomäki K, Blomqvist C, Margolin S, Kosma V-M, Hartikainen JM, Kataja V, Hatse S, Wildiers H, Smeets A, Figueroa J, Chanock SJ, Lissowska J, Li J, Humphreys K, Phillips K-A, Linn S, Cornelissen S, van den Broek SAJ, Kang D, Choi J-Y, Park SK, Yoo K-Y, Hsiung C-N, Wu P-E, Hou M-F, Shen C-Y, Teo SH, Taib NAM, Yip CH, Ho GF, Matsuo K, Ito H, Iwata H, Tajima K, Dunning AM, Benitez J, Czene K, Sucheston LE, Maishman T, Tapper WJ, Eccles D, Easton DF, Schmidt MK, Chang-Claude J (2015) Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy. Breast Cancer Res.  https://doi.org/10.1186/s13058-015-0522-2 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Li J, Lindström LS, Foo JN, Rafiq S, Schmidt MK, Pharoah PDP, Michailidou K, Dennis J, Bolla MK, Wang Q, Van Veer LJVT, Cornelissen S, Rutgers E, Southey MC, Apicella C, Dite GS, Hopper JL, Fasching PA, Haeberle L, Ekici AB, Beckmann MW, Blomqvist C, Muranen TA, Aittomäki K, Lindblom A, Margolin S, Mannermaa A, Kosma V-M, Hartikainen JM, Kataja V, Chenevix-Trench G, Phillips K-A, McLachlan S-A, Lambrechts D, Thienpont B, Smeets A, Wildiers H, Chang-Claude J, Flesch-Janys D, Seibold P, Rudolph A, Giles GG, Baglietto L, Severi G, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Kristensen V, Alnæs GIG, Borresen-Dale A-L, Nord S, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Devilee P, Tollenaar R, Seynaeve C, Hooning M, Kriege M, Hollestelle A, van den Ouweland A, Li Y, Hamann U, Torres D, Ulmer HU, Rüdiger T, Shen C-Y, Hsiung C-N, Wu P-E, Chen S-T, Teo SH, Taib NAM, Har Yip C, Fuang Ho G, Matsuo K, Ito H, Iwata H, Tajima K, Kang D, Choi J-Y, Park SK, Yoo K-Y, Maishman T, Tapper WJ, Dunning A, Shah M, Luben R, Brown J, Chuen Khor C, Eccles DM, Nevanlinna H, Easton D, Humphreys K, Liu J, Hall P, Czene K, Investigators k (2014) 2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy. Nat Commun.  https://doi.org/10.1038/ncomms5051 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Jeong H, Ryu Y-j, An J, Lee Y, Kim A (2012) Epithelial-mesenchymal transition in breast cancer correlates with high histological grade and triple-negative phenotype. Histopathology 60(6B):E87–E95.  https://doi.org/10.1111/j.1365-2559.2012.04195.x CrossRefPubMedGoogle Scholar
  65. 65.
    Asiedu MK, Ingle JN, Behrens MD, Radisky DC, Knutson KL (2011) TGFbeta/TNF(alpha)-mediated epithelial-mesenchymal transition generates breast cancer stem cells with a claudin-low phenotype. Cancer Res 71(13):4707–4719.  https://doi.org/10.1158/0008-5472.CAN-10-4554 CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Bhola NE, Balko JM, Dugger TC, Kuba MG, Sanchez V, Sanders M, Stanford J, Cook RS, Arteaga CL (2013) TGF-beta inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Investig 123(3):1348–1358.  https://doi.org/10.1172/JCI65416 CrossRefPubMedGoogle Scholar
  67. 67.
    Ghoshal K, Harazono Y, Muramatsu T, Endo H, Uzawa N, Kawano T, Harada K, Inazawa J, Kozaki K-i (2013) miR-655 is an EMT-suppressive MicroRNA targeting ZEB1 and TGFBR2. PLoS ONE 8(5):e62757.  https://doi.org/10.1371/journal.pone.0062757 CrossRefGoogle Scholar
  68. 68.
    Wang J, Liang S, Duan X (2018) Molecular mechanism of miR-153 inhibiting migration, invasion and epithelial-mesenchymal transition of breast cancer by regulating transforming growth factor beta (TGF-β) signaling pathway. J Cell Biochem 120(6):9539–9546.  https://doi.org/10.1002/jcb.28230 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Glauco Akelinghton Freire Vitiello
    • 1
  • Marla Karine Amarante
    • 1
  • Bruna Karina Banin-Hirata
    • 1
  • Clodoaldo Zago Campos
    • 2
    • 5
  • Karen Brajão de Oliveira
    • 1
  • Roberta Losi-Guembarovski
    • 3
  • Maria Angelica Ehara Watanabe
    • 1
    • 4
    Email author
  1. 1.Department of Pathological SciencesBiological Sciences Center, Londrina State UniversityLondrinaBrazil
  2. 2.Department of Clinical ResearchLondrina Cancer HospitalLondrinaBrazil
  3. 3.Department of General BiologyBiological Sciences Center, Londrina State UniversityLondrinaBrazil
  4. 4.Laboratory of DNA Polymorphisms and Immunology, Department of Pathological SciencesBiological Sciences Center, Londrina State UniversityLondrinaBrazil
  5. 5.Department of Clinical Medicine, Health Sciences CenterLondrina State UniversityLondrinaBrazil

Personalised recommendations