Comparative Clinical Pathology

, Volume 28, Issue 1, pp 183–188 | Cite as

Expression of interleukin-15 in canine mammary carcinoma: relationships with histologic grades, Bcl-2, recurrence, and overall survival

  • Massoud Rezaee Oghazi
  • Mohsen MalekiEmail author
  • Ahmad Reza Movassaghi
  • Zahra Kamyabi-Moghaddam
Original Article


Spontaneous tumors arising from mammary tissue are considered the most common tumor in female dogs and are of great importance both in veterinary and comparative medicine. Interleukin-15 is a cytokine involved in many physiologic processes such as activation of immune cells, autoimmune diseases, and cancer pathogenesis; however, the role of interleukin-15 in canine mammary cancers has not been well understood. We designed this study to examine the expression of interleukin-15 (IL-15) in canine mammary carcinoma by means of immunohistochemistry and any possible association with histologic malignancy grades, Bcl-2 expression, tumor recurrence, and overall survival. Results revealed that 14 (46.66%) of tumor samples strongly express IL-15, 7 cases (23.33%) moderately, and 9 cases showed weak immunoreactivity (30%). The expression of interleukin-15 is increased in canine mammary tumors in comparison to healthy tissues (p < 0.05). Additionally, interleukin-15 higher expression is significantly in relationship with high histologic grade (p < 0.05), high Bcl-2 expression (p < 0.05), and shorter overall survival (p < 0.05), but not with tumor recurrence (p > 0.05). Interleukin-15 could have a role mammary carcinogenesis in dogs but more studies are needed to understand its exact roles.


Canine Histologic grade Immunohistochemistry Interleukin-15 Mammary carcinoma Survival 



This study was funded by Ferdowsi University of Mashhad.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.


  1. Faisal Adhami, Jason C Steel, Morris JC 2012 Interleukin-15 expression in lung cancer. In: ASCO Annual Meeting,Google Scholar
  2. Adunyah SE, Wheeler BJ, Cooper RS (1997) Evidence for the involvement of LCK and MAP kinase (ERK-1) in the signal transduction mechanism of interleukin-15. Biochem Biophys Res Commun 232:754–758. CrossRefGoogle Scholar
  3. Bancroft GJ (1993) The role of natural killer cells in innate resistance to infection. Curr Opin Immunol 5:503–510. CrossRefGoogle Scholar
  4. Barzegar C, Meazza R, Pereno R, Pottin-Clemenceau C, Scudeletti M, Brouty-Boyé D, Doucet C, Taoufik Y, Ritz J, Musselli C, Mishal Z, Jasmin C, Indiveri F, Ferrini S, Azzarone B (1998) IL-15 is produced by a subset of human melanomas, and is involved in the regulation of markers of melanoma progression through juxtacrine loops. Oncogene 16:2503–2512. CrossRefGoogle Scholar
  5. Cory S, Huang DC, Adams JM (2003) The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22:8590–8607. CrossRefGoogle Scholar
  6. Dhillon AS, Hagan S, Rath O, Kolch W (2007) MAP kinase signalling pathways in cancer. Oncogene 26:3279–3290CrossRefGoogle Scholar
  7. Dobbeling U, Dummer R, Laine E, Potoczna N, Qin JZ, Burg G (1998) Interleukin-15 is an autocrine/paracrine viability factor for cutaneous T-cell lymphoma cells. Blood 92:252–258Google Scholar
  8. Fehniger TA, Caligiuri MA (2001) Interleukin 15: biology and relevance to human disease. Blood 97:14–32CrossRefGoogle Scholar
  9. Gillgrass A, Gill N, Babian A, Ashkar AA (2014) The absence or overexpression of IL-15 drastically alters breast cancer metastasis via effects on NK cells, CD4 T cells, and macrophages. J Immunol 193:6184–6191. CrossRefGoogle Scholar
  10. Gross A, McDonnell JM, Korsmeyer SJ (1999) BCL-2 family members and the mitochondria in apoptosis. Genes Dev 13:1899–1911CrossRefGoogle Scholar
  11. Hodge DL, Yang J, Buschman MD, Schaughency PM, Dang H, Bere W, Yang Y, Savan R, Subleski JJ, Yin XM, Loughran TP, Young HA (2009) Interleukin-15 enhances proteasomal degradation of bid in normal lymphocytes: implications for large granular lymphocyte leukemias. Cancer Res 69:3986–3994. CrossRefGoogle Scholar
  12. Huntington ND, Puthalakath H, Gunn P, Naik E, Michalak EM, Smyth MJ, Tabarias H, Degli-Esposti MA, Dewson G, Willis SN, Motoyama N, Huang DCS, Nutt SL, Tarlinton DM, Strasser A (2007) Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. Nat Immunol 8:856–863. CrossRefGoogle Scholar
  13. Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Silvennoinen O (1995) Signaling through the hematopoietic cytokine receptors. Annu Rev Immunol 13:369–398. CrossRefGoogle Scholar
  14. Johnston JA, Bacon CM, Finbloom DS, Rees RC, Kaplan D, Shibuya K, Ortaldo JR, Gupta S, Chen YQ, Giri JD (1995) Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. Proc Natl Acad Sci U S A 92:8705–8709CrossRefGoogle Scholar
  15. Khanna C, Lindblad-Toh K, Vail D, London C, Bergman P, Barber L, Breen M, Kitchell B, McNeil E, Modiano JF, Niemi S, Comstock KE, Ostrander E, Westmoreland S, Withrow S (2006) The dog as a cancer model. Nat Biotechnol 24:1065–1066Google Scholar
  16. Kim JH, Yu CH, Yhee JY, Im KS, Sur JH (2010) Lymphocyte infiltration, expression of interleukin (IL) -1, IL-6 and expression of mutated breast cancer susceptibility gene-1 correlate with malignancy of canine mammary tumours. Journal of comparative pathology 142:177-186.
  17. Kumaraguruparan R, Prathiba D, Nagini S (2006) Of humans and canines: immunohistochemical analysis of PCNA, Bcl-2, p53, cytokeratin and ER in mammary tumours. Res Vet Sci 81:218–224. CrossRefGoogle Scholar
  18. Kuniyasu H, Ohmori H, Sasaki T, Sasahira T, Yoshida K, Kitadai Y, Fidler IJ (2003) Production of interleukin 15 by human colon cancer cells is associated with induction of mucosal hyperplasia, angiogenesis, and metastasis. Clin Cancer Res 9:4802–4810Google Scholar
  19. Lollini P-L, Palmieri G, de Giovanni C, Landuzzi L, Nicoletti G, Rossi I, Griffoni C, Frabetti F, Scotlandi K, Benini S, Baldini N, Santoni A, Nanni P (1997) Expression of interleukin 15 (IL-15) in human rhabdomyosarcoma, osteosarcoma and Ewing's sarcoma. Int J Cancer 71:732–736.<732::AID-IJC7>3.0.CO;2-S CrossRefGoogle Scholar
  20. Meazza R, Verdiani S, Biassoni R, Coppolecchia M, Gaggero A, Orengo AM, Colombo MP, Azzarone B, Ferrini S (1996) Identification of a novel interleukin-15 (IL-15) transcript isoform generated by alternative splicing in human small cell lung cancer cell lines. Oncogene 12:2187–2192Google Scholar
  21. Misdorp W (1999) Histological classification of mammary tumors of the dog and the cat. Armed Forces Institute of Pathology,Google Scholar
  22. Misdorp W (2002) Tumors of the mammary gland. In: DJ M (ed) tumors in domestic animals. 4th edn. Iowa State Press, Ames, IA, pp 575–606, 764Google Scholar
  23. Mishra A, Liu S, Sams GH, Curphey DP, Santhanam R, Rush LJ, Schaefer D, Falkenberg LG, Sullivan L, Jaroncyk L, Yang X, Fisk H, Wu LC, Hickey C, Chandler JC, Wu YZ, Heerema NA, Chan KK, Perrotti D, Zhang J, Porcu P, Racke FK, Garzon R, Lee RJ, Marcucci G, Caligiuri MA (2012) Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation. Cancer Cell 22:645–655. CrossRefGoogle Scholar
  24. Mishra A, Sullivan L, Caligiuri MA (2014) Molecular pathways: Interleukin-15 signaling in health and in cancer. Clin Cancer Res 20:2044–2050. CrossRefGoogle Scholar
  25. Miyazaki T et al (1994) Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science (New York, NY) 266:1045–1047CrossRefGoogle Scholar
  26. Miyazaki T, Liu ZJ, Kawahara A, Minami Y, Yamada K, Tsujimoto Y, Barsoumian EL, Perlmutter RM, Taniguchi T (1995) Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation. Cell 81:223–231CrossRefGoogle Scholar
  27. Munson L, Moresco A (2007) Comparative pathology of mammary gland cancers in domestic and wild animals. Breast Dis 28:7–21CrossRefGoogle Scholar
  28. O'Brien MA, Kirby R (2008) Apoptosis: a review of pro-apoptotic and anti-apoptotic pathways and dysregulation in disease. J Vet Emerg Crit Care 18:572–585. CrossRefGoogle Scholar
  29. Queiroga FL, Raposo T, Carvalho MI, Prada J, Pires I (2011) Canine mammary tumours as a model to study human breast cancer: most recent findings. In Vivo 25:455–465Google Scholar
  30. Rautela J, Huntington ND (2016) IL-15 signaling in NK cell cancer immunotherapy. Curr Opin Immunol 44:1–6. CrossRefGoogle Scholar
  31. Rezaee M, Movassaghi AR, Dehghani H (2017a) Strong expression of interleukin-17 is associated with higher histologic grades in canine mammary carcinoma. Comp Clin Pathol 26:477–481. CrossRefGoogle Scholar
  32. Rezaee M, Movassaghi AR, Maleki M (2017b) Immunohistochemical expression of transforming growth factor Beta-1 in canine mammary carcinomas: its relationships with histologic grading, survival rate, and recurrence. Comparative Clinical Pathology:1-6 doi:
  33. Sanders A, Ye L, Wei X, Mansel R, Jiang W (2011) P1-01-08: expression of Interleukin-15 (IL-15) and the IL-15 receptor in human breast cancer. Cancer Research 71:P1-01-08
  34. Sen B, Johnson FM (2011) Regulation of Src family kinases in human cancers. Journal of Signal Transduction 2011:14–14. CrossRefGoogle Scholar
  35. Shenoy AR, Kirschnek S, Häcker G (2014) IL-15 regulates Bcl-2 family members Bim and Mcl-1 through JAK/STAT and PI3K/AKT pathways in T cells. Eur J Immunol 44:2500–2507CrossRefGoogle Scholar
  36. Shokoohi M, Shoorei H, Soltani M, Abtahi-Eivari SH, Salimnejad R, Moghimian M (2018) Protective effects of the hydroalcoholic extract of Fumaria parviflora on testicular injury induced by torsion/detorsion in adult rats.e13047.
  37. Shoorei H, Khaki A, Ainehchi N, Hassanzadeh Taheri MM, Tahmasebi M, Seyedghiasi G, Ghoreishi Z, Shokoohi M, Khaki AA, Abbas Raza SH (2018) Effects of Matricaria chamomilla extract on growth and maturation of isolated mouse ovarian follicles in a three-dimensional culture system. Chin Med J 131:218–225. CrossRefGoogle Scholar
  38. Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA (2004) JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia 18:189–218. CrossRefGoogle Scholar
  39. Steinway SN, Loughran TP (2013) Targeting IL-15 in large granular lymphocyte leukemia. Expert Rev Clin Immunol 9:405–408. CrossRefGoogle Scholar
  40. Thomas SJ, Snowden JA, Zeidler MP, Danson SJ (2015) The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br J Cancer 113:365–371. CrossRefGoogle Scholar
  41. Tinhofer I, Marschitz I, Henn T, Egle A, Greil R (2000) Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma. Blood 95:610–618Google Scholar
  42. Trinchieri G (1997) Cytokines acting on or secreted by macrophages during intracellular infection (IL-10, IL-12, IFN-gamma). Curr Opin Immunol 9:17–23. CrossRefGoogle Scholar
  43. Trinder P, Seitzer U, Gerdes J, Seliger B, Maeurer M (1999) Constitutive and IFN-gamma regulated expression of IL-7 and IL-15 in human renal cell cancer. Int J Oncol 14:23–31Google Scholar
  44. Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM (1984) Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science (New York, NY) 226:1097-1099Google Scholar
  45. Yang WY, Liu CH, Chang CJ, Lee CC, Chang KJ, Lin CT (2006) Proliferative activity, apoptosis and expression of oestrogen receptor and Bcl-2 oncoprotein in canine mammary gland tumours. J Comp Pathol 134:70–79. CrossRefGoogle Scholar
  46. Zuccari DA, Castro R, Gelaleti GB, Mancini UM (2011) Interleukin-8 expression associated with canine mammary tumors. Genet Mol Res : GMR 10:1522–1532CrossRefGoogle Scholar

Copyright information

© Springer-Verlag London Ltd., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pathobiology, Faculty of Veterinary MedicineFerdowsi University of MashhadMashhadIran
  2. 2.Faculty of veterinary medicineUniversity of TehranTehranIran

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