Breast Cancer Research and Treatment

, Volume 102, Issue 2, pp 129–135 | Cite as

Significance of interleukin-6 (IL-6) in breast cancer (review)

  • Heike KnüpferEmail author
  • Rainer Preiß


Cytokines are factors that are known to have both tumor-promoting and inhibitory effects on breast cancer growth depending presumably on their relative concentrations and the presence of other modulating factors. Different cytokines play an important role in controlling the immune system. Interleukin-6 (IL-6) is a pleiotropic cytokine with obviously tumor-promoting and tumor-inhibitory effects. Here, we review the role of IL-6 in in vitro experiments of breast tumor cells, in breast tumor tissues (BTs) and assess its potential as a prognostic indicator in breast cancer patients. A literature search was conducted using PubMed, restricted to articles published in English language. In summary, results regarding the effect of IL-6 on breast tumor cells and on BTs are not unique indicating both tumor-promoting and inhibitory effects of IL-6. Concerning patients’ serum IL-6 levels, data are surprisingly unique showing IL-6 to be a negative prognosticator in breast tumor patients.


Breast cancer Interleukin-6 Prognostic factor 


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  1. 1.
    Hortobagyi GN (2000) Developments in chemotherapy of breast cancer. Cancer 88(Suppl 12):3073–3079PubMedCrossRefGoogle Scholar
  2. 2.
    Esteva FJ, Valero V, Pusztai L, Boehnke-Michaud L, Buzdar AU, Hortobagyi GN (2001) Chemotherapy of metastatic breast cancer: what to expect in 2001 and beyond. Oncologist 6(2):133–146PubMedCrossRefGoogle Scholar
  3. 3.
    Dranoff G (2004) Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 4(1):11–22PubMedCrossRefGoogle Scholar
  4. 4.
    Ben-Baruch A (2003) Host microenvironment in breast cancer development: inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor-microenvironment interactions. Breast Cancer Res 5(1):31–36PubMedCrossRefGoogle Scholar
  5. 5.
    Kishimoto T, Taga T, Akira S (1994) Cytokine signal transduction. Cell 76(2):253–262PubMedCrossRefGoogle Scholar
  6. 6.
    Stewart TH (1996) Evidence for immune facilitation of breast cancer growth and for the immune promotion of oncogenesis in breast cancer. Medicina (B Aires) 56(Suppl 1):13–24Google Scholar
  7. 7.
    Allan CP, Turtle CJ, Mainwaring PN, Pyke C, Hart DN (2004) The immune response to breast cancer, and the case for DC immunotherapy. Cytotherapy 6(2):154–163PubMedGoogle Scholar
  8. 8.
    Purohit A, Newman SP, Reed MJ (2002) The role of cytokines in regulating estrogen synthesis: implications for the etiology of breast cancer. Breast Cancer Res 4(2):65–69PubMedCrossRefGoogle Scholar
  9. 9.
    Leu CM, Wong FH, Chang C, Huang SF, Hu CP (2003) Interleukin-6 acts as an antiapoptotic factor in human esophageal carcinoma cells through the activation of both STAT3 and mitogen-activated protein kinase pathways. Oncogene 22(49):7809–7818PubMedCrossRefGoogle Scholar
  10. 10.
    Brocke-Heidrich K, Kretzschmar AK, Pfeifer G, Henze C, Loffler D, Koczan D, Thiesen HJ, Burger R, Gramatzki M, Horn F (2004) Interleukin-6-dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family-independent survival pathway closely associated with Stat3 activation. Blood 103(1):242–251PubMedCrossRefGoogle Scholar
  11. 11.
    Conze D, Weiss L, Regen PS, Bhushan A, Weaver D, Johnson P, Rincon M (2001) Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells. Cancer Res 61(24):8851–8858PubMedGoogle Scholar
  12. 12.
    Haverty AA, Harmey JH, Redmond HP, Bouchier-Hayes DJ (1997) Interleukin-6 upregulates GP96 expression in breast cancer. J Surg Res 69(1):145–149PubMedCrossRefGoogle Scholar
  13. 13.
    Chiu JJ, Sgagias MK, Cowan KH (1996) Interleukin 6 acts as a paracrine growth factor in human mammary carcinoma cell lines. Clin Cancer Res 2(1):215–221PubMedGoogle Scholar
  14. 14.
    Arihiro K, Oda H, Kaneko M, Inai K (2000) Cytokines facilitate chemotactic motility of breast carcinoma cells. Breast Cancer 7(3):221–230PubMedGoogle Scholar
  15. 15.
    Verhasselt B, Van Damme J, van Larebeke N, Put W, Bracke M, De Potter C, Mareel M (1992) Interleukin-1 is a motility factor for human breast carcinoma cells in vitro: additive effect with interleukin-6. Eur J Cell Biol 59(2):449–457PubMedGoogle Scholar
  16. 16.
    Asgeirsson KS, Olafsdottir K, Jonasson JG, Ogmundsdottir HM (1998) The effects of IL-6 on cell adhesion and e-cadherin expression in breast cancer. Cytokine 10(9):720–728PubMedCrossRefGoogle Scholar
  17. 17.
    Bhat-Nakshatri P, Campbell RA, Patel NM, Newton TR, King AJ, Marshall MS, Ali S, Nakshatri H (2004) Tumour necrosis factor and PI3-kinase control oestrogen receptor alpha protein level and its transrepression function. Br J Cancer 90(4):853–859PubMedCrossRefGoogle Scholar
  18. 18.
    Miki S, Iwano M, Miki Y, Yamamoto M, Tang B, Yokokawa K, Sonoda T, Hirano T, Kishimoto T (1989) Interleukin-6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas. FEBS Lett 250(2):607–610PubMedCrossRefGoogle Scholar
  19. 19.
    Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H et al (1988) Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 332(6159):83–85PubMedCrossRefGoogle Scholar
  20. 20.
    Eustace D, Han X, Gooding R, Rowbottom A, Riches P, Heyderman E (1993) Interleukin-6 (IL-6) functions as an autocrine growth factor in cervical carcinomas in vitro. Gynecol Oncol 50(1):15–19PubMedCrossRefGoogle Scholar
  21. 21.
    Miles SA, Rezai AR, Salazar-Gonzalez JF, Vander Meyden M, Stevens RH, Logan DM, Mitsuyasu RT, Taga T, Hirano T, Kishimoto T et al (1990) AIDS Kaposi sarcoma-derived cells produce and respond to interleukin 6. Proc Natl Acad Sci USA 87(11):4068–4072PubMedCrossRefGoogle Scholar
  22. 22.
    Shimizu S, Hirano T, Yoshioka R, Sugai S, Matsuda T, Taga T, Kishimoto T, Konda S (1988) Interleukin-6 (B-cell stimulatory factor 2)-dependent growth of a Lennert’s lymphoma-derived T-cell line (KT-3). Blood 72(5):1826–1828PubMedGoogle Scholar
  23. 23.
    Yee C, Biondi A, Wang XH, Iscove NN, de Sousa J, Aarden LA, Wong GG, Clark SC, Messner HA, Minden MD (1989) A possible autocrine role for interleukin-6 in two lymphoma cell lines. Blood 74(2):798–804PubMedGoogle Scholar
  24. 24.
    Hirano T (1998) Interleukin-6 and its receptor: ten years later. Int Rev Immunol 16:249–284PubMedGoogle Scholar
  25. 25.
    Wang Q, Horiatis D, Pinski J (2004) Interleukin-6 inhibits the growth of prostate cancer xenografts in mice by the process of neuroendocrine differentiation. Int J Cancer 111(4):508–513PubMedCrossRefGoogle Scholar
  26. 26.
    Kobel M, Budianto D, Schmitt WD, Borsi L, Siri A, Hauptmann S Influence of various cytokines on adhesion and migration of the colorectal adenocarcinoma cell line HRT–18.Oncology 68(1):33–39Google Scholar
  27. 27.
    Poppenborg H, Knupfer MM, Galla HJ, Ernst J, Wolff A (1999) In vitro modulation of cisplatin resistance by cytokines. Cytokine 11(9):689–695PubMedCrossRefGoogle Scholar
  28. 28.
    Honma S, Shimodaira K, Shimizu Y, Tsuchiya N, Saito H, Yanaihara T, Okai T (2002) The influence of inflammatory cytokines on estrogen production and cell proliferation in human breast cancer cells. Endocr J 49(3):371–377PubMedGoogle Scholar
  29. 29.
    Shen WH, Zhou JH, Broussard SR, Freund GG, Dantzer R, Kelley KW (2002) Proinflammatory cytokines block growth of breast cancer cells by impairing signals from a growth factor receptor. Cancer Res 62(16):4746–4756PubMedGoogle Scholar
  30. 30.
    Kishimoto T, Hirano T (1988) Molecular regulation of B lymphocyte response. Annu Rev Immunol 6:485–512PubMedCrossRefGoogle Scholar
  31. 31.
    Takenawa J, Kaneko Y, Fukumoto M, Fukatsu A, Hirano T, Fukuyama H, Nakayama H, Fujita J, Yoshida O (1991) Enhanced expression of interleukin-6 in primary human renal cell carcinomas. J Natl Cancer Inst 83(22):1668–1672PubMedCrossRefGoogle Scholar
  32. 32.
    Marrogi AJ, Munshi A, Merogi AJ, Ohadike Y, El-Habashi A, Marrogi OL, Freeman SM (1997) Study of tumor infiltrating lymphocytes and transforming growth factor-beta as prognostic factors in breast carcinoma. Int J Cancer 74(5):492–501PubMedCrossRefGoogle Scholar
  33. 33.
    Knupfer H, Schmidt R, Stanitz D, Brauckhoff M, Schonfelder M, Preiss R (2004) CYP2C and IL-6 expression in breast cancer. Breast 13(1):28–34PubMedCrossRefGoogle Scholar
  34. 34.
    Ueno T, Toi M, Saji H, Muta M, Bando H, Kuroi K, Koike M, Inadera H, Matsushima K (2000) Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin Cancer Res 6(8):3282–3289PubMedGoogle Scholar
  35. 35.
    Irahara N, Miyoshi Y, Taguchi T, Tamaki Y, Noguchi S (2006) Quantitative analysis of aromatase mRNA expression derived from various promoters (I.4, I.3, PII and I.7) and its association with expression of TNF-alpha, IL-6 and COX-2 mRNAs in human breast cancer. Int J Cancer 118(8):1915–1921PubMedCrossRefGoogle Scholar
  36. 36.
    Crichton MB, Nichols JE, Zhao Y, Bulun SE, Simpson ER (1996) Expression of transcripts of interleukin-6 and related cytokines by human breast tumors, breast cancer cells, and adipose stromal cells. Mol Cell Endocrinol 118(1–2):215–220PubMedCrossRefGoogle Scholar
  37. 37.
    Purohit A, Ghilchik MW, Duncan L, Wang DY, Singh A, Walker MM, Reed MJ (1995) Aromatase activity and interleukin-6 production by normal and malignant breast tissues. J Clin Endocrinol Metab 80(10):3052–3058PubMedCrossRefGoogle Scholar
  38. 38.
    Green AR, Green VL, White MC, Speirs V (1997) Expression of cytokine messenger RNA in normal and neoplastic human breast tissue: identification of interleukin-8 as a potential regulatory factor in breast tumours. Int J Cancer 72(6):937–941PubMedCrossRefGoogle Scholar
  39. 39.
    Basolo F, Conaldi PG, Fiore L, Calvo S, Toniolo A (1993) Normal breast epithelial cells produce interleukins 6 and 8 together with tumor-necrosis factor: defective IL6 expression in mammary carcinoma. Int J Cancer 55(6):926–930PubMedCrossRefGoogle Scholar
  40. 40.
    Fontanini G, Campani D, Roncella M, Cecchetti D, Calvo S, Toniolo A, Basolo F (1999) Expression of interleukin 6 (IL-6) correlates with oestrogen receptor in human breast carcinoma. Br J Cancer 80(3–4):579–584PubMedCrossRefGoogle Scholar
  41. 41.
    Karczewska A, Nawrocki S, Breborowicz D, Filas V, Mackiewicz A (2000) Expression of interleukin-6, interleukin-6 receptor, and glycoprotein 130 correlates with good␣prognoses for patients with breast carcinoma. Cancer 88(9):2061–2071PubMedCrossRefGoogle Scholar
  42. 42.
    Garcia-Tunon I, Ricote M, Ruiz A, Fraile B, Paniagua R, Royuela M (2005) IL-6, its receptors and its relationship with bcl-2 and bax proteins in infiltrating and in situ human breast carcinoma. Histopathology 47(1):82–89PubMedCrossRefGoogle Scholar
  43. 43.
    Kozlowski L, Zakrzewska I, Tokajuk P, Wojtukiewicz MZ (2003) Concentration of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10) in blood serum of breast cancer patients. Rocz Akad Med Bialymst 48:82–84PubMedGoogle Scholar
  44. 44.
    Yokoe T, Iino Y, Morishita Y (2000) Trends of IL-6 and IL-8 levels in patients with recurrent breast cancer: preliminary report. Breast Cancer 7(3):187–190PubMedCrossRefGoogle Scholar
  45. 45.
    Jiang XP, Yang DC, Elliott RL, Head JF (2000) Reduction in serum IL-6 after vacination of breast cancer patients with tumour-associated antigens is related to estrogen receptor status. Cytokine 12(5):458–465PubMedCrossRefGoogle Scholar
  46. 46.
    Nishimura R, Nagao K, Miyayama H, Matsuda M, Baba K, Matsuoka Y, Yamashita H, Fukuda M, Mizumoto T, Hamamoto R (2000) An analysis of serum interleukin-6 levels to predict benefits of medroxyprogesterone acetate in advanced or recurrent breast cancer. Oncology 59(2):166–173PubMedCrossRefGoogle Scholar
  47. 47.
    Bozcuk H, Uslu G, Samur M, Yildiz M, Ozben T, Ozdogan M, Artac M, Altunbas H, Akan I, Savas B (2004) Tumour necrosis factor-alpha, interleukin-6, and fasting serum insulin correlate with clinical outcome in metastatic breast cancer patients treated with chemotherapy. Cytokine 27(2–3):58–65PubMedCrossRefGoogle Scholar
  48. 48.
    Zhang GJ, Adachi I (1999) Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma. Anticancer Res 19(2B):1427–1432PubMedGoogle Scholar
  49. 49.
    Salgado R, Junius S, Benoy I, Van Dam P, Vermeulen P, Van Marck E, Huget P, Dirix LY (2003) Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int J Cancer 103(5):642–646PubMedCrossRefGoogle Scholar
  50. 50.
    Bachelot T, Ray-Coquard I, Menetrier-Caux C, Rastkha M, Duc A, Blay JY (2003) Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients. Br J Cancer 88(11):1721–1726PubMedCrossRefGoogle Scholar
  51. 51.
    Jablonska E, Kiluk M, Markiewicz W, Piotrowski L, Grabowska Z, Jablonski J (2001) TNF-alpha, IL-6 and their soluble receptor serum levels and secretion by neutrophils in␣cancer patients. Arch Immunol Ther Exp (Warsz) 49(1):63–69Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  1. 1.Institute of Clinical PharmacologyUniversity of LeipzigLeipzigGermany

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