Molecular Biology Reports

, Volume 45, Issue 5, pp 741–750 | Cite as

CXCL12 chemokine and CXCR4 receptor: association with susceptibility and prognostic markers in triple negative breast cancer

  • Alda Losi Guembarovski
  • Roberta Losi GuembarovskiEmail author
  • Bruna Karina Banin Hirata
  • Glauco Akelinghton Freire Vitiello
  • Karen Mayumi Suzuki
  • Mayara Tiemi Enokida
  • Maria Angelica Ehara Watanabe
  • Edna Maria Vissoci Reiche
Original Article


CXCL12/CXCR4 signaling has been implicated in breast carcinogenesis, and genetic polymorphisms in these molecules have been associated with different types of cancer. The present study analyzed genetic polymorphisms in CXCL12 (rs1801157, G > A) and CXCR4 (rs2228014, C > T) and CXCR4 immunostaining in tumor tissues from patients with triple negative breast cancer (TNBC) aiming to evaluate their possible role in its’ susceptibility and prognosis. Genetic polymorphisms were analyzed in 59 TNBC patients and 150 control women; age-adjusted logistic regression showed no association when variants were considered in isolation; however, a statistically significant interaction was noted for heterozygosis for both allelic variants increasing the odds for TNBC (CXCL12-GA by CXCR4-CT: OR 7.23; 95% CI 1.15–45.41; p = 0.035). CXCL12 polymorphism was correlated negatively with proliferation index (Ki67) (Tau-b = − 0.406; p = 0.006). CXCR4 immunostaining was evaluated in 37 TNBC patients (22 with paired tumor-normal adjacent tissue). CXCR4 was detected more intensely in cell cytoplasm than in membrane, and was more expressed in tumor than in normal adjacent tissues, although not statistically significant. CXCR4 expression on the membrane of tumor cells was correlated positively with histopathological grade (Tau-b = 0.271; p = 0.036) and negatively with lymph node metastasis (Tau-b = − 0.478; p = 0.036). The present study indicates that CXCL12 and CXCR4 polymorphisms and CXCR4 immunostaining might have susceptibility and prognostic roles in TNBC pathogenesis.


Triple-negative breast cancer CXCL12 CXCR4 Genetic polymorphism Prognosis Immunohistochemistry 



We acknowledge all the volunteer donors involved in the study and the Londrina State University Clinical Hospital (HC-UEL), Orlando Sestari primary health care unit and Londrina Cancer Hospital (HCL) staff for support during sample collection. The present study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 303186/2015-1 process), Fundação Araucária (1027/2013 agreement) and Coordenadoria de Pós-Graduação, Londrina State University - PROPPG-UEL.

Supplementary material

11033_2018_4215_MOESM1_ESM.docx (1.7 mb)
Supplementary material 1 (DOCX 1769 KB)


  1. 1.
    Kurebayashi J (2009) Possible treatment strategies for triple-negative breast cancer on the basis of molecular characteristics. Breast Cancer 16(4):275–280. CrossRefPubMedGoogle Scholar
  2. 2.
    Sleeman KE, Kendrick H, Ashworth A, Isacke CM, Smalley MJ (2006) CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells. Breast cancer research: BCR 8(1):R7. CrossRefPubMedGoogle Scholar
  3. 3.
    Maegawa RO, Tang SC (2010) Triple-negative breast cancer: unique biology and its management. Cancer Investig 28(8):878–883. CrossRefGoogle Scholar
  4. 4.
    Dawson SJ, Provenzano E, Caldas C (2009) Triple negative breast cancers: clinical and prognostic implications. Eur J Cancer 45 Suppl 1:27–40. CrossRefGoogle Scholar
  5. 5.
    Karnoub AE, Weinberg RA (2006) Chemokine networks and breast cancer metastasis. Breast Dis 26:75–85CrossRefPubMedGoogle Scholar
  6. 6.
    Hinton CV, Avraham S, Avraham HK (2010) Role of the CXCR4/CXCL12 signaling axis in breast cancer metastasis to the brain. Clin Exp Metastasis 27(2):97–105. CrossRefPubMedGoogle Scholar
  7. 7.
    Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA (1996) A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med 184(3):1101–1109CrossRefPubMedGoogle Scholar
  8. 8.
    Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ (2006) A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med 203(9):2201–2213. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    de Oliveira Cavassin GG, De Lucca FL, Delgado Andre N, Covas DT, Pelegrinelli Fungaro MH, Voltarelli JC, Watanabe MA (2004) Molecular investigation of the stromal cell-derived factor-1 chemokine in lymphoid leukemia and lymphoma patients from Brazil. Blood Cells Mol Dis 33(1):90–93. CrossRefPubMedGoogle Scholar
  10. 10.
    de Oliveira KB, Oda JM, Voltarelli JC, Nasser TF, Ono MA, Fujita TC, Matsuo T, Watanabe MA (2009) CXCL12 rs1801157 polymorphism in patients with breast cancer, Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma. J Clin Lab Anal 23(6):387–393. CrossRefPubMedGoogle Scholar
  11. 11.
    Winkler C, Modi W, Smith MW, Nelson GW, Wu X, Carrington M, Dean M, Honjo T, Tashiro K, Yabe D, Buchbinder S, Vittinghoff E, Goedert JJ, O’Brien TR, Jacobson LP, Detels R, Donfield S, Willoughby A, Gomperts E, Vlahov D, Phair J, O’Brien SJ (1998) Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC). Science 279(5349):389–393CrossRefPubMedGoogle Scholar
  12. 12.
    do Val Carneiro JL, Nixdorf SL, Mantovani MS, Herrera AC, Aoki MN, Amarante MK, Fabris BA, Pelegrinelli Fungaro MH, Ehara Watanabe MA, do Amaral ACDS (2009) Plasma malondialdehyde levels and CXCR4 expression in peripheral blood cells of breast cancer patients. J Cancer Res Clin Oncol 135(8):997–1004. CrossRefPubMedGoogle Scholar
  13. 13.
    Oda JM, de Oliveira KB, Guembarovski RL, de Lima KW, da Silva do Amaral Herrera AC, Guembarovski AL, Sobrinho WJ, Derossi DR, Watanabe MA (2012) TGF-beta polymorphism and its expression correlated with CXCR4 expression in human breast cancer. Mol Biol Rep 39(12):10131–10137CrossRefPubMedGoogle Scholar
  14. 14.
    Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik A (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824):50–56. CrossRefPubMedGoogle Scholar
  15. 15.
    Luker KE, Luker GD (2006) Functions of CXCL12 and CXCR4 in breast cancer. Cancer Lett 238(1):30–41. CrossRefPubMedGoogle Scholar
  16. 16.
    Zhang M, Liu HX, Teng XD, Wang HB, Cui J, Jia SS, Gu XY, Li ZG (2012) The differences in CXCR4 protein expression are significant for the five molecular subtypes of breast cancer. Ultrastruct Pathol 36(6):381–386. CrossRefPubMedGoogle Scholar
  17. 17.
    Petersen DC, Glashoff RH, Shrestha S, Bergeron J, Laten A, Gold B, Rensburg EJ, Dean M, Hayes V (2005) Risk for HIV-1 infection associated with a common CXCL12 (SDF-1) polymorphism and CXCR4 variation in an African population. J Acquir Immune 40(5):6Google Scholar
  18. 18.
    Teicher BA, Fricker SP (2010) CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res 16(11):2927–2931. CrossRefPubMedGoogle Scholar
  19. 19.
    Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ (2012) WHO Classification of Tumours, vol 4, 240 pp. ISBN: 9283224337Google Scholar
  20. 20.
    Sobin LH, Gospodarowicz MK, Wittekind C (2009) TNM classification of malignant tumours. Wiley, HobokenGoogle 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 (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):e48-72. PubMedCrossRefGoogle Scholar
  22. 22.
    Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, 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. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Okuyama Kishima M, Brajao de Oliveira K, Ariza CB, de Oliveira CE, Losi Guembarovski R, Banin Hirata BK, de Almeida FC, Vitiello GA, Trugilo KP, Guembarovski AF, Jorge Sobrinho W, Campos CZ, Watanabe MA (2015) Genetic polymorphism and expression of CXCR4 in breast cancer. Anal Cell Pathol (Amst) 2015:289510.
  24. 24.
    Lin G-T, Tseng H-F, Yang C-H, Hou M-F, Chuang L-Y, Tai H-T, Tai M-H, Cheng Y-H, Wen C-H, Liu C-S, Huang C-J, Wang C-L, Chang H-W (2009) Combinational polymorphisms of seven CXCL12-related genes are protective against breast cancer in Taiwan. OMICS J Integr Biol 13(2):165–172. CrossRefGoogle Scholar
  25. 25.
    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. CrossRefPubMedGoogle Scholar
  26. 26.
    Kakinuma T, Hwang ST (2006) Chemokines, chemokine receptors, and cancer metastasis. J Leukoc Biol 79(4):639–651. CrossRefPubMedGoogle Scholar
  27. 27.
    Salvatore P, Pagliarulo C, Colicchio R, Napoli C (2010) CXCR4-CXCL12-dependent inflammatory network and endothelial progenitors. Curr Med Chem 17(27):3019–3029CrossRefPubMedGoogle Scholar
  28. 28.
    Dupont VN, Gentien D, Oberkampf M, De Rycke Y, Blin N (2007) A gene expression signature associated with metastatic cells in effusions of breast carcinoma patients. Int J Cancer 121(5):1036–1046. CrossRefPubMedGoogle Scholar
  29. 29.
    Dimberg J, Hugander A, Lofgren S, Wagsater D (2007) Polymorphism and circulating levels of the chemokine CXCL12 in colorectal cancer patients. Int J Mol Med 19(1):11–15PubMedGoogle Scholar
  30. 30.
    de Oliveira KB, Guembarovski RL, Oda JM, Mantovani MS, Carrera CM, Reiche EM, Voltarelli JC, da Silva do Amaral Herrera AC, Watanabe MA (2011) CXCL12 rs1801157 polymorphism and expression in peripheral blood from breast cancer patients. Cytokine 55(2):260–265. CrossRefPubMedGoogle Scholar
  31. 31.
    Quaini F, Schulz M, Karpova D, Spohn G, Damert A, Seifried E, Binder V, Bönig H (2015) Variant rs1801157 in the 3′UTR of SDF-1ß does not explain variability of healthy-donor G-CSF responsiveness. PLos ONE 10(3):e0121859. CrossRefGoogle Scholar
  32. 32.
    ENCODE Project Consortium (2004).The ENCODE (ENCyclopedia of DNA Elements) project Science 306 (5696):636–640. CrossRefGoogle Scholar
  33. 33.
    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. PubMedCentralCrossRefGoogle Scholar
  34. 34.
    Cleator S, Heller W, Coombes RC (2007) Triple-negative breast cancer: therapeutic options. Lancet Oncol 8(3):235–244. CrossRefPubMedGoogle Scholar
  35. 35.
    Pemberton NC, Paneesha S, Hiller L, Starczynski J, Hooper L, Pepper C, Pratt G, Fegan C (2006) The SDF-1 G> A polymorphism at position 801 plays no role in multiple myeloma but may contribute to an inferior cause-specific survival in chronic lymphocytic leukemia. Leuk Lymphoma 47(7):1239–1244. CrossRefPubMedGoogle Scholar
  36. 36.
    Maley SN, Schwartz SM, Johnson LG, Malkki M, Du Q, Daling JR, Li SS, Zhao LP, Petersdorf EW, Madeleine MM (2009) Genetic variation in CXCL12 and risk of cervical carcinoma: a population-based case-control study. Int J Immunogenet 36(6):367–375. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Vazquez-Lavista LG, Lima G, Gabilondo F, Llorente L (2009) Genetic association of monocyte chemoattractant protein 1 (MCP-1)-2518 polymorphism in Mexican patients with transitional cell carcinoma of the bladder. Urology 74(2):414–418. CrossRefPubMedGoogle Scholar
  38. 38.
    Hassan S, Baccarelli A, Salvucci O, Basik M (2008) Plasma stromal cell-derived factor-1: host derived marker predictive of distant metastasis in breast cancer. Clin Cancer Res 14(2):446–454. CrossRefPubMedGoogle Scholar
  39. 39.
    Kruszyna L, Lianeri M, Rubis B, Knula H, Rybczynska M, Grodecka-Gazdecka S, Jagodzinski PP (2010) CXCL12-3′ G801A polymorphism is not a risk factor for breast cancer. DNA Cell Biol 29(8):5. CrossRefGoogle Scholar
  40. 40.
    Razmkhah M, Talei AR, Doroudchi M, Khalili-Azad T, Ghaderi A (2005) Stromal cell-derived factor-1 (SDF-1) alleles and susceptibility to breast carcinoma. Cancer Lett 225(2):261–266. CrossRefPubMedGoogle Scholar
  41. 41.
    Wu Y, Zhang C, Xu W, Zhang J, Zheng Y, Lu Z, Liu D, Jiang K (2016) CXC motif chemokine receptor 4 gene polymorphism and cancer risk. Medicine 95(49):e5317. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Kucukgergin C, Isman FK, Dasdemir S, Cakmakoglu B, Sanli O, Gokkusu C, Seckin S (2012) The role of chemokine and chemokine receptor gene variants on the susceptibility and clinicopathological characteristics of bladder cancer. Gene 511(1):7–11. CrossRefPubMedGoogle Scholar
  43. 43.
    Lee YL, Kuo WH, Lin CW, Chen W, Cheng WE, Chen SC, Shih CM (2011) Association of genetic polymorphisms of CXCL12/SDF1 gene and its receptor, CXCR4, to the susceptibility and prognosis of non-small cell lung cancer. Lung Cancer 73(2):147–152. CrossRefPubMedGoogle Scholar
  44. 44.
    Cacina C, Bulgurcuoglu-Kuran S, Iyibozkurt AC, Yaylim-Eraltan I, Cakmakoglu B (2012) Genetic variants of SDF-1 and CXCR4 genes in endometrial carcinoma. Mol Biol Rep 39(2):1225–1229. CrossRefPubMedGoogle Scholar
  45. 45.
    Cai C, Wang LH, Dong Q, Wu ZJ, Li MY, Sun YH (2013) Association of CXCL12 and CXCR4 gene polymorphisms with the susceptibility and prognosis of renal cell carcinoma. Tissue Antigens 82(3):165–170. CrossRefPubMedGoogle Scholar
  46. 46.
    Martin MP, Carrington M, Dean M, O’Brien SJ, Sheppard HW, Wegner SA, Michael NL (1998) CXCR4 polymorphisms and HIV-1 pathogenesis. J Acquir Immune Defic Syndr Hum Retrovirol 19(4):430CrossRefPubMedGoogle Scholar
  47. 47.
    Broeks A, Schmidt MK, Sherman ME, Couch FJ, Hopper JL, Dite GS, Apicella C, Smith LD, Hammet F, Southey MC, Van’t Veer LJ, de Groot R, Smit VTHBM., Fasching PA, Beckmann MW, Jud S, Ekici AB, Hartmann A, Hein AF, Schulz-Wendtland R, Burwinkel B, Marme F, Schneeweiss A, Sinn H-P, Sohn C, Tchatchou S, Bojesen SE, Nordestgaard BG, Flyger H, Ørsted DD, Kaur-Knudsen D, Milne RL, Pérez JIA, Zamora P, Rodríguez PM, Benítez J, Brauch H, Justenhoven CF, Ko Y-D, Hamann U, Fischer H-P, Brüning T, Pesch B, Chang-Claude J, Wang-Gohrke S, Bremer M, Karstens JH, Hillemanns P, Dörk T, Nevanlinna HA, Heikkinen T, Heikkilä P, Blomqvist C, Aittomäki K, Aaltonen K, Lindblom A, Margolin S, Mannermaa A, Kosma V-M, Kauppinen JM, Kataja VF, Auvinen P, Eskelinen M, Soini Y, Chenevix-Trench G, Spurdle AB, Beesley J, Chen X, Holland H, Lambrechts D, Claes B, Vandorpe T, Neven P, Wildiers H, Flesch-Janys D, Hein R, Löning TF, Kosel M, Fredericksen ZS, Wang X, Giles GG, Baglietto L, Severi G, McLean C, Haiman CA, Henderson BE, Le Marchand L, Kolonel LN, Grenaker Alnæs G, Kristensen V, Børresen-Dale A-LF, Hunter DJ, Hankinson SE, Andrulis IL, Marie Mulligan A, O’Malley FP, Devilee P, Huijts PEA, Tollenaar RAEM., Van Asperen CJ, Seynaeve CS, Chanock SJ, Lissowska J, Brinton L, Peplonska B, Figueroa J, Yang XR, Hooning MJ, Hollestelle AF, Oldenburg RA, Jager A, Kriege M, Ozturk B, van Leenders GJLH., Hall P, Czene K, Humphreys K, Liu J, Cox A, Connley D, Cramp HE, Cross SS, Balasubramanian SP, Reed MWR, Dunning AM, Easton DF, Humphreys MK, Caldas C, Blows F, Driver K, Provenzano E, Lubinski J, Jakubowska A, Huzarski T, Byrski T, Cybulski C, Gorski B, Gronwald J, Brennan P, Sangrajrang S, Gaborieau V, Shen C-Y, Hsiung C-N, Yu J-C, Chen S-T, Hsu G-C, Hou M-F, Huang C-S, Anton-Culver H, Ziogas A, Pharoah PDP, Garcia-Closas M (2011) Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium. Human Mol Genet 20 (16):3289–3303. CrossRefGoogle Scholar
  48. 48.
    de Oliveira KB, Guembarovski RL, Guembarovski A, Herrera ACDD., Sobrinho WJ, Ariza CB, Watanabe MAE (2013) CXCL12, CXCR4 and IFN gamma genes expression: implications for proinflammatory microenvironment of breast cancer. Clin Exp Med 13(3):211–219. CrossRefPubMedGoogle Scholar
  49. 49.
    Hattermann K, Holzenburg E, Hans F, Lucius R, Held-Feindt J, Mentlein R (2014) Effects of the chemokine CXCL12 and combined internalization of its receptors CXCR4 and CXCR7 in human MCF-7 breast cancer cells. Cell Tissue Res 357(1):253–266. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Kato M, Kitayama J, Kazama S, Nagawa H (2003) Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma. Breast Cancer Res 5(5):R144-150. CrossRefGoogle Scholar
  51. 51.
    Chen HW, Du CW, Wei XL, Khoo US, Zhang GJ (2013) Cytoplasmic CXCR4 high-expression exhibits distinct poor clinicopathological characteristics and predicts poor prognosis in triple-negative breast cancer. Curr Mol Med 13(3):410–416PubMedGoogle Scholar
  52. 52.
    Sivrikoz ON, Doganay L, Sivrikoz UK, Karaarslan S, Sanal SM (2013) Distribution of CXCR4 and gamma-catenin expression pattern in breast cancer subtypes and their relationship to axillary nodal involvement. Pol J Pathol 64(4):253–259. CrossRefPubMedGoogle Scholar
  53. 53.
    Chu QD, Panu L, Holm NT, Li BD, Johnson LW, Zhang S (2010) High chemokine receptor CXCR4 level in triple negative breast cancer specimens predicts poor clinical outcome. J Surg Res 159(2):689–695. CrossRefPubMedGoogle Scholar
  54. 54.
    Yu S, Wang X, Liu G, Zhu X, Chen Y (2013) High level of CXCR4 in triple-negative breast cancer specimens associated with a poor clinical outcome. Acta Med Okayama 67(6):369–375PubMedGoogle Scholar
  55. 55.
    Mukherjee D, Zhao J (2013) The Role of chemokine receptor CXCR4 in breast cancer metastasis. Am J Cancer Res 3(1):46–57PubMedPubMedCentralGoogle Scholar
  56. 56.
    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 (2016) TGF-beta1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis. Oncogene 35(6):748–760. CrossRefPubMedGoogle Scholar
  57. 57.
    Liu F, Lang R, Wei J, Fan Y, Cui L, Gu F, Guo X, Pringle GA, Zhang X, Fu L (2009) Increased expression of SDF-1/CXCR4 is associated with lymph node metastasis of invasive micropapillary carcinoma of the breast. Histopathology 54(6):741–750. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Alda Losi Guembarovski
    • 1
  • Roberta Losi Guembarovski
    • 2
    • 4
    Email author
  • Bruna Karina Banin Hirata
    • 3
  • Glauco Akelinghton Freire Vitiello
    • 3
  • Karen Mayumi Suzuki
    • 3
  • Mayara Tiemi Enokida
    • 3
  • Maria Angelica Ehara Watanabe
    • 3
    return OK on get
  • Edna Maria Vissoci Reiche
    • 1
  1. 1.Department of Pathology, Clinical and Toxicological Analyses, Health Sciences CenterLondrina State UniversityLondrinaBrazil
  2. 2.Department of General Biology, Biological Sciences CenterLondrina State UniversityLondrinaBrazil
  3. 3.Department of Pathological Sciences, Biological Sciences CenterLondrina State UniversityLondrinaBrazil
  4. 4.Laboratory of Studies and Applications of DNA Polymorphisms, Biological Sciences CenterLondrina State UniversityLondrinaBrazil

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