Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Diversity of KIRs in invasive breast cancer patients and healthy controls along with the clinical significance in ER/PR/HER2+ patients

Abstract

Killer cell immunoglobulin-like receptors (KIR) consists of activating and inhibitory genes are essential for natural killer cell education. To determine the association of KIRs with susceptibility to invasive Breast cancer (BC), genotyping of 16 KIRs was performed by sequence-specific primers-polymerase chain reaction in 226 confirmed cases of BC with defined estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) status and 226 healthy controls (CNs). We observed a lower frequency of 2DL1 and 2DS4del along with increased frequency of 2DS4fl in cases compared to CNs. Further analysis revealed a higher frequency of KIR2DL2, 2DS1, 2DS2,3DS1 in ER+ cases, 2DL2, 2DL5 in PR+ and 2DL1 in HER2+ cases compared to CNs. The detrimental role of KIR2DS4fl was observed in ER+ and PR+ cases whereas 2DS4del confers protection against ER+, PR+, and HER2+ cases. We noted the predisposing role of Bx genotype, KIR2DS1, 2DS2, 2DS5, 2DL2, 2DL5 for lymphatic invasion in ER+ cases along with a higher rate of lymph node metastasis (LNM) in carriers of Bx genotype and KIR2DS1 in ER+ cases. We suggest a link between B haplotype associated genes with the increased risk of lymphatic invasion and LNM, particularly in ER+ cases of BC.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med. 2004;23:1111–30.

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Kamińska M, Ciszewski T, Łopacka-Szatan K, Miotła P, Starosławska E. Breast cancer risk factors. Prz menopauzalny= Menopause Rev. 2015;14:196.

    Article  Google Scholar 

  3. 3.

    Feng Y, Spezia M, Huang S, Yuan C, Zeng Z, Zhang L, et al. Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes Dis. 2018;5:77–106.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P, et al. Breast cancer. Nat Rev Dis Prim. 2019;5:66.

    PubMed  Article  Google Scholar 

  5. 5.

    Saadatmand S, Bretveld R, Siesling S, Tilanus-Linthorst MM. Influence of tumour stage at breast cancer detection on survival in modern times: population based study in 173,797 patients. BMJ. 2015;351:h4901.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Dias AS, Almeida CR, Helguero LA, Duarte IF. Metabolic crosstalk in the breast cancer microenvironment. Eur J Cancer. 2019;121:154–71.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Pfeifer C, Highton AJ, Peine S, Sauter J, Schmidt AH, Bunders MJ, et al. Natural killer cell education is associated with a distinct metabolic profile. Front Immunol. 2018;9:3020.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331:44–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Sternberg-Simon M, Brodin P, Pickman Y, Önfelt B, Kärre K, Malmberg K-J, et al. Natural killer cell inhibitory receptor expression in humans and mice: a closer look. Front Immunol. 2013;4:65.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. 10.

    Augusto DG. The impact of KIR polymorphism on the risk of developing cancer: not as strong as imagined? Front Genet. 2016;7:121.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11.

    Dorak MT. Role of natural killer cells and killer immunoglobulin-like receptor polymorphisms. Methods Mol. Med. 2007;134:123–44.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Pende D, Falco M, Vitale M, Cantoni C, Vitale C, Munari E et al. Killer Ig-like receptors (KIRs): their role in NK cell modulation and developments leading to their clinical exploitation. Front Immunol. 2019;10.

  13. 13.

    Rajalingam R. Diversity of killer cell immunoglobulin-like receptors and disease. Clin Lab Med. 2018;38:637–53.

    PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Uhrberg M. The KIR gene family: life in the fast lane of evolution. Eur J Immunol. 2005;35:10–5.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Le CT, et al. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood. 2010;116:2411–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Middleton D, Gonzelez F. The extensive polymorphism of KIR genes. Immunology. 2010;129:8–19.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Ivarsson MA, Michaëlsson J, Fauriat C. Activating killer cell Ig-like receptors in health and disease. Front Immunol. 2014;5:184.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. 18.

    Rajagopalan S, Long EO. The direct binding of a p58 killer cell inhibitory receptor to human histocompatibility leukocyte antigen (HLA)-Cw4 exhibits peptide selectivity. J Exp Med. 1997;185:1523–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Boudreau JE, Hsu KC. Natural killer cell education in human health and disease. Curr Opin Immunol. 2018;50:102–11.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Ozturk OG, Gun FD, Polat G. Killer cell immunoglobulin-like receptor genes in patients with breast cancer. Med Oncol. 2012;29:511–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Alomar SY, Alkhuriji A, Trayhyrn P, Alhetheel A, Al-jurayyan A, Mansour L. Association of the genetic diversity of killer cell immunoglobulin-like receptor genes and HLA-C ligand in Saudi women with breast cancer. Immunogenetics. 2017;69:69–76.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Jobim MR, Jobim M, Salim PH, Portela P, Jobim LF, Leistner-Segal S, et al. Analysis of KIR gene frequencies and HLA class I genotypes in breast cancer and control group. Hum Immunol. 2013;74:1130–3.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Jamali E, Barani S, Yousefinejad F, Ariafar A, Talei GR, Ghaderi A. KIRs gene content diversity in Iranians with urothelial bladder cancer. Mol Biol Rep. 2018;45:713–9.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Yousefinejad F, Jowkar F, Barani S, Jamali E, Mahmoudi E, Ramezani A, et al. Killer cell immunoglobulin-like receptors (KIRs) genotype and haplotype analysis in iranians with non-melanoma skin cancers. Iran Biomed J. 2019;23:330.

    PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Barani S, Taghipour M, Ghaderi AJI. Positive association of Bx genotype, KIR2L5, KIR2DS5 and full-length KIR2DS4 with the risk of meningioma. Immunobiology. 2020;225:151900.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Barani S, Hosseini SV, Ghaderi A. Activating and inhibitory killer cell immunoglobulin like receptors (KIR) genes are involved in an increased susceptibility to colorectal adenocarcinoma and protection against invasion and metastasis. Immunobiology. 2019;224:681–6.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Barani S, Khademi B, Ashouri E, Ghaderi A. KIR2DS1, 2DS5, 3DS1 and KIR2DL5 are associated with the risk of head and neck squamous cell carcinoma in Iranians. Hum Immunol. 2018;79:218–23.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Barani S, Khademi B, Ghaderi A. KIR2DS4, KIR2DL2, and KIR2DS4del are linked with basaloid tumors, lymph node metastasis, advanced stage and metastatic risk in head and neck squamous cell carcinoma. Exp Mol Pathol. 2020;112:104345.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Chavan VR, Chaudhari D, Ahir S, Ansari Z, Mehta P, Mania-Pramanik JJBri. Variations in KIR genes: a study in HIV-1 serodiscordant couples. Biomed Res Int. 2014;2014:891402.

    PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Giebel S, Nowak I, Wojnar J, Krawczyk-Kulis M, Holowiecki J, Kyrcz-Krzemien S, et al. Association of KIR2DS4 and its variant KIR1D with leukemia. Leukemia. 2008;22:2129.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Bao X, Hou L, Sun A, Qiu Q, Yuan X, Chen M, et al. The impact of KIR2DS4 alleles and the expression of KIR in the development of acute GVHD after unrelated allogeneic hematopoietic SCT. Bone Marrow Transpl. 2010;45:1435.

    CAS  Article  Google Scholar 

  32. 32.

    Deng Z, Zhao J, Cai S, Qi Y, Yu Q, Martin MP, et al. Natural killer cells offer differential protection from three kinds of leukemia in southern Chinese Han. Front Immunol. 2019;10:1646.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    La Nasa G, Greco M, Littera R, Oppi S, Celeghini I, Caria R, et al. The favorable role of homozygosity for killer immunoglobulin-like receptor (KIR) A haplotype in patients with advanced-stage classic Hodgkin lymphoma. J Hematol. 2016;9:26.

    Google Scholar 

  34. 34.

    Perez M, Cabrera T, Lopez Nevot M, Gomez M, Peran F, Ruiz‐Cabello F, et al. Heterogeneity of the expression of class I and II HLA antigens in human breast carcinoma. Int J Immunogenetics. 1986;13:247–54.

    CAS  Article  Google Scholar 

  35. 35.

    Wintzer H, Benzing M, Von Kleist S. Lacking prognostic significance of β 2-microglobulin, MHC class I and class II antigen expression in breast carcinomas. Br J cancer. 1990;62:289.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Fleming K, McMichael A, Morton J, Woods J, McGee JOD. Distribution of HLA class 1 antigens in normal human tissue and in mammary cancer. J Clin Pathol. 1981;34:779–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Hernandez EG, Partida-Rodriguez O, Camorlinga-Ponce M, Nieves-Ramirez M, Ramos-Vega I, Torres J, et al. Genotype B of killer cell immunoglobulin-like receptor is related with gastric cancer lesions. Sci Rep. 2018;8:6104.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Rajalingam R. Human diversity of killer cell immunoglobulin-like receptors and disease. Korean J Hematol. 2011;46:216–28.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Mamessier E, Sylvain A, Thibult M-L, Houvenaeghel G, Jacquemier J, Castellano R, et al. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J Clin Investig. 2011;121:3609–22.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Kristensen AB, Kent SJ, Parsons MS. Contribution of NK cell education to both direct and anti-HIV-1 antibody-dependent NK cell functions. J Virol. 2018;92:e02146–17.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Bao X, Wang M, Zhou H, Zhang H, Wu X, Yuan X, et al. Donor killer immunoglobulin-like receptor profile Bx1 imparts a negative effect and centromeric B-specific gene motifs render a positive effect on standard-risk acute myeloid leukemia/myelodysplastic syndrome patient survival after unrelated donor hematopoietic stem cell transplantation. Biol Blood Marrow Transpl. 2016;22:232–9.

    CAS  Article  Google Scholar 

  42. 42.

    Levinson RD, Yung M, Meguro A, Ashouri E, Yu F, Mizuki N, et al. KIR and HLA genotypes implicated in reduced killer lymphocytes immunity are associated with Vogt-Koyanagi-Harada disease. PloS ONE. 2016;11:e0160392.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. 43.

    Zhuang Y, Song Y, Zhu C, Zhang Y, Wang D, Nie X, et al. Association of KIR genotypes and haplotypes with syphilis in a Chinese Han population. Scand J Immunol. 2012;75:361–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Stern M, Hadaya K, Hönger G, Martin PY, Steiger J, Hess C, et al. Telomeric rather than centromeric activating KIR genes protect from cytomegalovirus infection after kidney transplantation. Am J Transplant. 2011;11:1302–7.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16:626.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Segovia-Mendoza M, Morales-Montor J. Immune tumor microenvironment in breast cancer and the participation of estrogens and its receptors into cancer physiopathology. Front Immunol. 2019;10:348.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. 47.

    Lee HJ, Song IH, Park IA, Heo S-H, Kim Y-A, Ahn J-H, et al. Differential expression of major histocompatibility complex class I in subtypes of breast cancer is associated with estrogen receptor and interferon signaling. Oncotarget. 2016;7:30119.

    PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Vilches C, Castano J, Gomez‐Lozano N, Estefania E. Facilitation of KIR genotyping by a PCR‐SSP method that amplifies short DNA fragments. Tissue Antigens. 2007;70:415–22.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Ashouri E, Ghaderi A, Reed E, Rajalingam R. A novel duplex SSP–PCR typing method for KIR gene profiling. Tissue Antigens. 2009;74:62–7.

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

The study was financially supported by Shiraz University of Medical Sciences [grant number: 1396-01-01-16590] and partly by Shiraz Institute for Cancer Research [grant number: ICR-100-509]. Ethical approval of the research was confirmed by Medical Ethics Committee of Shiraz University of Medical Sciences [IR.SUMS.REC.1397.573]. The present study was part of a MSc thesis written by Marjan Hematian Larki.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Abbas Ghaderi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hematian Larki, M., Barani, S., Talei, AR. et al. Diversity of KIRs in invasive breast cancer patients and healthy controls along with the clinical significance in ER/PR/HER2+ patients. Genes Immun 21, 380–389 (2020). https://doi.org/10.1038/s41435-020-00117-1

Download citation

Further reading

Search

Quick links