Skip to main content

Advertisement

SpringerLink
Log in

CCR2-V64I genetic polymorphism: a possible involvement in HER2+ breast cancer

  • Review Article
  • Published:
Clinical and Experimental Medicine Aims and scope Submit manuscript

Abstract

Many tumor cells express chemokines and chemokine receptors, and these molecules can affect both tumor progression and anti-tumor immune response. Genetic polymorphisms of some chemokine receptors were found to be closely related to malignant tumors, especially in metastasis process, including breast cancer (BC). Considering this, it was investigated a possible role for CCR2-V64I (C–C chemokine receptor 2) and CCR5-Δ32 (C–C chemokine receptor 5) genetic variants in BC context. Patients were divided into subgroups according to immunohistochemical profile of estrogen (ER) and progesterone (PR) receptors and the human epidermal growth factor receptor 2 (HER2) overexpression. No significant associations were found in relation to susceptibility (CCR2-V64I: OR 1.32; 95 % CI 0.57–3.06; CCR5-∆32: OR 1.04; 95 % CI 0.60–1.81), clinical outcome (tumor size, lymph nodes commitment and/or distant metastasis, TNM staging and nuclear grade) or therapeutic response (recurrence and survival). However, it was found a significant correlation between CCR2-V64I allelic variant and HER2 immunohistochemical positive samples (p = 0.026). All in all, we demonstrate, for the first time, a positive correlation between CCR2 receptor gene polymorphism and a subgroup of BC related to poor prognosis, which deserves further investigation in larger samples for validation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11 [database on the Internet] 2012. Accessed: 25/01/2014.

  2. Citri A, Skaria KB, Yarden Y. The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp Cell Res. 2003;284(1):54–65.

    Article  CAS  PubMed  Google Scholar 

  3. de la Cruz-Merino L, Barco-Sanchez A, Carrasco FH et al. New insights into the role of the immune microenvironment in breast carcinoma. Clin Dev Immunol. 2013.

  4. Charo IF, Myers SJ, Herman A, Franci C, Connolly AJ, Coughlin SR. Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails. Proc Natl Acad Sci USA. 1994;91(7):2752–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sanders SK, Crean SM, Boxer PA, Kellner D, LaRosa GJ, Hunt SW. Functional differences between monocyte chemotactic protein-1 receptor A and monocyte chemotactic protein-1 receptor B expressed in a Jurkat T cell. J Immunol. 2000;165(9):4877–83.

    Article  CAS  PubMed  Google Scholar 

  6. Fang WB, Jokar I, Zou A, Lambert D, Dendukuri P, Cheng N. CCL2/CCR2 chemokine signaling coordinates survival and motility of breast cancer cells through Smad3 protein- and p42/44 mitogen-activated protein kinase (MAPK)-dependent mechanisms. J Biol Chem. 2012;287(43):36593–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B. CCR5 is characteristic of Th1 lymphocytes. Nature. 1998;391(6665):344–5.

    Article  CAS  PubMed  Google Scholar 

  8. Manes S, Mira E, Colomer R, et al. CCR5 expression influences the progression of human breast cancer in a p53-dependent manner. J Exp Med. 2003;198(9):1381–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Velasco-Velazquez M, Jiao XM, De la Fuente M, et al. CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res. 2012;72(15):3839–50.

    Article  CAS  PubMed  Google Scholar 

  10. Velasco-Velazquez M, Pestell RG. The CCL5/CCR5 axis promotes metastasis in basal breast cancer. Oncoimmunology. 2013;2(4):e23660.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ugurel S, Schrama D, Keller G, et al. Impact of the CCR5 gene polymorphism on the survival of metastatic melanoma patients receiving immunotherapy. Cancer Immunol Immunother. 2008;57(5):685–91.

    Article  CAS  PubMed  Google Scholar 

  12. Chen MK, Yeh KT, Chiou HL, Lin CW, Chung TT, Yang SF. CCR2-64I gene polymorphism increase susceptibility to oral cancer. Oral Oncol. 2011;47(7):577–82.

    Article  CAS  PubMed  Google Scholar 

  13. Kucukgergin C, Isman FK, Cakmakoglu B, Sanli O, Seckin S. Association of polymorphisms in MCP-1, CCR2, and CCR5 genes with the risk and clinicopathological characteristics of prostate cancer. DNA Cell Biol. 2012;31(8):1418–24.

    Article  CAS  PubMed  Google Scholar 

  14. Nakayama EE, Tanaka Y, Nagai Y, Iwamoto A, Shioda T. A CCR2-V641 polymorphism affects stability of CCR2A isoform. Aids. 2004;18(5):729–38.

    Article  CAS  PubMed  Google Scholar 

  15. Kostrikis LG, Huang YX, Moore JP, et al. A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation. Nat Med. 1998;4(3):350–3.

    Article  CAS  PubMed  Google Scholar 

  16. Barmania F, Pepper M. C–C chemokine receptor type five (CCR5): an emerging target for the control of HIV infection. Appl Transl Genomics. 2013;2:3–16.

    Article  CAS  Google Scholar 

  17. Zafiropoulos A, Crikas N, Passam AM, Spandidos DA. Significant involvement of CCR2-64I and CXCL12-3a in the development of sporadic breast cancer. J Med Genet. 2004;41(5).

  18. Span PN, Pollakis G, Paxton WA et al. Improved metastasis-free survival in nonadjuvantly treated postmenopausal breast cancer patients with chemokine receptor 5 del32 frameshift mutations. Int J Cancer. 2014.

  19. Sobin LH, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. 7th ed. Oxford: Wiley-Blackwell; 2009.

    Google Scholar 

  20. Wolff AC, Hammond ME, Hicks DG, et al. 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. 2013;31(31):3997–4013.

    Article  PubMed  Google Scholar 

  21. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28(16):2784–95.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Aoki MN, da Silva do Amaral Herrera AC, Amarante MK, do Val Carneiro JL, Fungaro MH, Watanabe MA. CCR5 and p53 codon 72 gene polymorphisms: implications in breast cancer development. Int J Mol Med. 2009;23(3):429–35.

    CAS  PubMed  Google Scholar 

  23. Sezgin I, Koksal B, Bagci G, Kurtulgan HK, Ozdemir O. CCR2 polymorphism in chronic renal failure patients requiring long-term hemodialysis. Intern Med. 2011;50(21):2457–61.

    Article  CAS  PubMed  Google Scholar 

  24. Rodriguez S, Gaunt TR, Day IN. Hardy–Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol. 2009;169(4):505–14.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4(7):540–50.

    Article  CAS  PubMed  Google Scholar 

  26. Zhang YM, Yao F, Yao XL, et al. Role of CCL5 in invasion, proliferation and proportion of CD44 +/CD24(−) phenotype of MCF-7 cells and correlation of CCL5 and CCR5 expression with breast cancer progression. Oncol Rep. 2009;21(4):1113–21.

    Article  CAS  PubMed  Google Scholar 

  27. Qian BZ, Li JF, Zhang H, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature. 2011;475(7355):222–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Attar R, Agachan B, Kuran SB, et al. Association of CCL2 and CCR2 gene variants with endometrial cancer in Turkish women. In vivo. 2010;24(2):243–8.

    CAS  PubMed  Google Scholar 

  29. Yeh CB, Tsai HT, Chen YC, et al. Genetic polymorphism of CCR2-64I increased the susceptibility of hepatocellular carcinoma. J Surg Oncol. 2010;102(3):264–70.

    Article  CAS  PubMed  Google Scholar 

  30. Zheng B, Wiklund F, Gharizadeh B, et al. Genetic polymorphism of chemokine receptors CCR2 and CCR5 in Swedish cervical cancer patients. Anticancer Res. 2006;26(5B):3669–74.

    CAS  PubMed  Google Scholar 

  31. Guleria K, Sharma S, Manjari M. Uppal MS, Singh NR, Sambyal V. p. R72P, PIN3 Ins16 bp Polymorphisms of TP53 and CCR5 Delta 32 in North Indian Breast Cancer Patients. Asian Pac J Cancer. 2012;13(7):3305–11.

    Article  Google Scholar 

  32. Degerli N, Yilmaz E, Bardakci F. The Delta 32 allele distribution of the CCR5 gene and its relationship with certain cancers in a Turkish population. Clin Biochem. 2005;38(3):248–52.

    Article  CAS  PubMed  Google Scholar 

  33. Gharagozloo M, Doroudchi M, Farjadian S, Pezeshki AM, Ghaderi A. The frequency of CCR5Delta32 and CCR2-64I in southern Iranian normal population. Immunol Lett. 2005;96(2):277–81.

    Article  CAS  PubMed  Google Scholar 

  34. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the Her-2/Neu proto-oncogene in human-breast and ovarian-cancer. Science. 1989;244(4905):707–12.

    Article  CAS  PubMed  Google Scholar 

  35. Bosher JM, Williams T, Hurst HC. The developmentally-regulated transcription factor Ap-2 Is involved in C-Erbb-2 overexpression in human mammary-carcinoma. Proc Natl Acad Sci USA. 1995;92(3):744–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jimenez F, Quinones MP, Martinez HG, et al. CCR2 plays a critical role in dendritic cell maturation: possible role of CCL2 and NF-kappa B. J Immunol. 2010;184(10):5571–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cao N, Li SY, Wang ZQ, et al. NF-kappa B-mediated HER2 overexpression in radiation-adaptive resistance. Radiat Res. 2009;171(1):9–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We acknowledge the volunteers who made this study possible. This study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq, the Fundação Araucária and the Coordenadoria de Pós-Graduação, Londrina State University—PROPPG-UEL. Bruna Karina Banin Hirata is a fellow of the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—CAPES, Brazil.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The protocol was approved by the Institutional Human Research Ethics Committee of the State University of Londrina, Paraná, Brazil (CEP/UEL 189/2013, CAAE 17123113400005231).

Informed consent

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

Author information

Authors and Affiliations

  1. Laboratory of Study and Application of DNA Polymorphisms, Department of Pathological Sciences, Biological Science Center, State University of Londrina, Pr 445 km 380 Celso Garcia Cid Highway, Londrina, PR, 86057-970, Brazil

    Bruna Karina Banin-Hirata, Roberta Losi-Guembarovski, Carlos Eduardo Coral de Oliveira & Maria Angelica Ehara Watanabe

  2. Medicine Course, Federal University of Mato Grosso do Sul, 1662 Capitão Olinto Mancini Avenue, Três Lagoas, MS, 79300-080, Brazil

    Julie Massayo Maeda Oda

  3. University Hospital of Londrina, Department of Medical Clinic and Post-Graduate Program of Health Sciences, State University of Londrina, 60 Robert Koch Avenue, Londrina, PR, 86038-440, Brazil

    Clodoaldo Zago Campos & Tânia Longo Mazzuco

  4. Cancer Hospital of Londrina, 378 Lucilla Ballalai Street, Londrina, PR, 86015-520, Brazil

    Clodoaldo Zago Campos & Jesus Roberto Ceribelli

  5. Department of Basic Health Sciences, State University of Maringá, Colombo Avenue, Maringá, PR, 87020-900, Brazil

    Sueli Donizete Borelli

Authors
  1. Bruna Karina Banin-Hirata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roberta Losi-Guembarovski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Julie Massayo Maeda Oda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carlos Eduardo Coral de Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Clodoaldo Zago Campos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tânia Longo Mazzuco
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sueli Donizete Borelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jesus Roberto Ceribelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maria Angelica Ehara Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria Angelica Ehara Watanabe.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Banin-Hirata, B.K., Losi-Guembarovski, R., Oda, J.M.M. et al. CCR2-V64I genetic polymorphism: a possible involvement in HER2+ breast cancer. Clin Exp Med 16, 139–145 (2016). https://doi.org/10.1007/s10238-015-0342-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10238-015-0342-9

Keywords

Search

Navigation