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Expression of Toll-like receptor 4 and beta 1 integrin in breast cancer

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Abstract

Toll-like receptor (TLR) 4 signaling pathway has been shown to support tumor cell growth in vitro and in vivo. Its stimulation on breast cancer cell lines induces β1 integrin and promotes tumor invasiveness. However, its role in predicting clinical behavior of tumor is not yet clarified. Therefore, we investigated TLR4 and β1 integrin expression on 133 primary breast cancer samples by immunohistochemistry and correlated it with overall survival and disease-free survival of patients as well as with clinicopathological characteristics of the tumor. We found higher β1 integrin expression in invasive lobular cancer in comparison with other tumor types. No significant association of TLR4 and β1 integrin expression with overall survival or disease-free survival was seen. Therefore, we conclude that expression of these markers is of biological interest but appears to be of little additional use as predictive clinical marker.

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References

  1. O’Neill LA. When signaling pathways collide: positive and negative regulation of toll-like receptor signal transduction. Immunity. 2008;29:12–20.

    Article  PubMed  Google Scholar 

  2. Huang B, Zhao J, Unkeless JC, Feng ZH, Xiong H. TLR signaling by tumor and immune cells: a double-edged sword. Oncogene. 2008;27(2):218–24.

    Article  PubMed  CAS  Google Scholar 

  3. Ren T, et al. Functional expression of TLR9 is associated to the metastatic potential of human lung cancer cell. Cancer Biol Ther. 2007;6(11):1704–9.

    Article  PubMed  CAS  Google Scholar 

  4. He W, et al. TLR4 signalling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. Mol Immunol. 2007;44(11):2850–9.

    Article  PubMed  CAS  Google Scholar 

  5. Zhang YB, et al. Increased expression of Toll-like receptors 4 and 9 in human lung cancer. Mol Biol Rep. 2009;36(6):1475–81.

    Article  PubMed  CAS  Google Scholar 

  6. Droemann D, et al. Human lung cancer cells express functionally active Toll-like receptor 9. Resp Res. 2005;6:1–10.

    Article  Google Scholar 

  7. Kelly MG, et al. TLR-4 signalling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res. 2006;66(7):3859–68.

    Article  PubMed  CAS  Google Scholar 

  8. Merrell MA, et al. Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity. Mol Cancer Res. 2006;4(7):437–47.

    Article  PubMed  CAS  Google Scholar 

  9. Ilvesaro JM, et al. Toll-like receptor 9 agonists stimulate prostate cancer invasion in vitro. Prostate. 2007;67:774–81.

    Article  PubMed  CAS  Google Scholar 

  10. Xie W, et al. Toll-like receptor 2 mediates invasion via activating NF-κB in MDA-MB-231 breast cancer cells. Biochem Biophys Res Commun. 2009;379(4):1027–32.

    Article  PubMed  CAS  Google Scholar 

  11. Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T. TLR3 can directly trigger apoptosis in human cancer cells. J Immunol. 2006;176(8):4894–901.

    PubMed  CAS  Google Scholar 

  12. Zaks-Zilberman M, Zaks TZ, Vogel SN. Induction of proinflammatory and chemokine genes by lipopolysaccharide and paclitaxel (Taxol) in murine and human breast cancer cell lines. Cytokine. 2001;15:156–65.

    Article  PubMed  CAS  Google Scholar 

  13. Stroinigg N, Srivastava MD. Modulation of toll-like receptor 7 and LL-37 expression in colon and breast epithelial cells by human beta-defensin-2. MD Allergy Asthma Proc. 2005;26(4):299–309.

    CAS  Google Scholar 

  14. Yang H, et al. Reduced expression of Toll-like receptor 4 inhibits human breast cancer cells proliferation and inflammatory cytokines secretion. J Exp Clin Cancer Res. 2010;29:92–9.

    PubMed  Google Scholar 

  15. Gonzalez-Reyes S, et al. Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis. BMC Cancer. 2010;10(1):665–74.

    Article  PubMed  CAS  Google Scholar 

  16. Harmey JH, et al. Lipopolysaccharide-induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion. Int J Cancer. 2002;101:415–22.

    Article  PubMed  CAS  Google Scholar 

  17. Wang JH, et al. Endotoxin/lipopolysaccharide activates NF-kappaB and enhances tumor cell adhesion and invasion through a beta 1 integrin-dependent mechanism. J Immunol. 2003;170:795–804.

    PubMed  CAS  Google Scholar 

  18. Hemler ME, Mannion BA, Berditchievski F. Association of TM4SF proteins with integrins:relevance to cancer. Biochem Biophys Acta. 1996;1287:67–71.

    PubMed  Google Scholar 

  19. Varmer JA, Cheresh DA. Integrins and cancer. Curr Opin Cell Biol. 1996;8:724–30.

    Article  Google Scholar 

  20. Arai K, Asakura T, Nemir P. Effect of local tumor removal and retained oncolysate on lung metastasis. J Surg Res. 1992;53:30–8.

    Article  PubMed  CAS  Google Scholar 

  21. Watson RW, Redmond HP, McCarthy J, Burke PE, Bouchier-Hayes D. Exposure of the peritoneal cavity to air regulates early inflammatory responses to surgery in a murine model. Br J Surg. 1995;82:1060–5.

    Article  PubMed  CAS  Google Scholar 

  22. Pidgeon GP, et al. The role of endotoxin/lipopolysaccharide in surgically induced tumour growth in a murine model of metastatic disease. Br J Cancer. 1999;81:1311–7.

    Article  PubMed  CAS  Google Scholar 

  23. Ridley AJ. Rho GTPases and cell migration. J Cell Sci. 2001;114(15):2713–22.

    PubMed  CAS  Google Scholar 

  24. Morini M, et al. The alpha 3 beta 1 integrin is associated with mammary carcinoma cell metastasis, invasion, and gelatinase B (MMP-9) activity. Int J Cancer. 2000;87(3):336–42.

    Article  PubMed  CAS  Google Scholar 

  25. Felding-Habermann B, et al. Involvement of tumor cell integrin alpha v beta 3 in hematogenous metastasis of human melanoma cells. Clin Exp Metastasis. 2002;19(5):427–36.

    Article  PubMed  CAS  Google Scholar 

  26. Hofmann UB, et al. Coexpression of integrin alpha (v) beta3 and matrix metalloproteinase-2 (MMP-2) coincides with MMP-2 activation: correlation with melanoma progression. J Invest Dermatol. 2000;115(4):625–32.

    Article  PubMed  CAS  Google Scholar 

  27. Hofmann UB, Westphal JR, Van Kraats AA, Ruiter DJ, Van Muijen GN. Expression of integrin alpha (v) beta (3) correlates with activation of membrane-type matrix metalloproteinase-1 (MT1-MMP) and matrix metalloproteinase-2 (MMP-2) in human melanoma cells in vitro and in vivo. Int J Cancer. 2000;87(1):12–9.

    Article  PubMed  CAS  Google Scholar 

  28. Miyamoto S, Teramoto H, Gutkind JS, Yamada KM. Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. J Cell Biol. 1996;135:1633–42.

    Article  PubMed  CAS  Google Scholar 

  29. Moro L, et al. Integrins induce activation of EGF receptor: role in MAP kinase induction and adhesion-dependent cell survival. EMBO J. 1998;17(22):6622–32.

    Article  PubMed  CAS  Google Scholar 

  30. Guo W, et al. Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell. 2006;126(3):489–502.

    Article  PubMed  CAS  Google Scholar 

  31. Gambaletta D, et al. Cooperative signaling between alpha (6) beta (4) integrin and ErbB-2 receptor is required to promote phosphatidylinositol 3-kinase-dependent invasion. Biol Chem. 2000;275(14):10604–10.

    Article  CAS  Google Scholar 

  32. Bill HM, et al. Epidermal growth factor receptor-dependent regulation of integrin-mediated signaling and cell cycle entry in epithelial cells. Mol Cell Biol. 2004;24(19):8586–99.

    Article  PubMed  CAS  Google Scholar 

  33. Yoon SO, Shin S, Lipscomb EA. A novel mechanism for integrin-mediated ras activation in breast carcinoma cells: the alpha 6 beta 4 integrin regulates ErbB2 translation and transactivates epidermal growth factor receptor/ErbB2 signaling. Cancer Res. 2006;66(5):2732–9.

    Article  PubMed  CAS  Google Scholar 

  34. Oshita F, et al. High expression of integrin ß1 and p53 is a greater poor prognostic factor than clinical stage in small-cell lung cancer. Am J Clin Oncol. 2004;27:215–9.

    Article  PubMed  CAS  Google Scholar 

  35. Bottger TC, et al. Prognostic value of immunohistochemical expression of ß-1 integrin in pancreatic carcinoma. Oncology. 1999;56:308–13.

    Article  PubMed  CAS  Google Scholar 

  36. Nikkola J, et al. Integrin chains ß1 and αv as prognostic factors in human metastatic melanoma. Melanoma Res. 2004;14:29–37.

    Article  PubMed  CAS  Google Scholar 

  37. Gui GP, et al. Integrin expression in primary breast cancer and its relation to axillary nodal status. Surgery. 1995;117:102–8.

    Article  PubMed  CAS  Google Scholar 

  38. Jonjic N, Lucin K, Krstulja M, Iternicka Z, Mustac E. Expression of ß-1 integrins on tumor cells of invasive ductal breast carcinoma. Pathol Res Pract. 1993;189:979–84.

    Article  PubMed  CAS  Google Scholar 

  39. Tavassoli FA, Devilee P. World health organisation classification of tumors. Lyon: IARC Press; 2003. p. 26.

    Google Scholar 

  40. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19:403–10.

    Article  PubMed  CAS  Google Scholar 

  41. Taylor CR. The current role of immunohistochemistry in diagnostic pathology. Adv Pathol Lab Med. 1994;7:59–65.

    CAS  Google Scholar 

  42. Bartlett JMS, et al. Evaluating HER2 amplification and overexpression in breast cancer. J Pathol. 2001;195:422–8.

    Article  PubMed  CAS  Google Scholar 

  43. Wang EL, et al. High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer. Br J Cancer. 2010;102(5):908–15.

    Article  PubMed  CAS  Google Scholar 

  44. White DE, Muller WJ. Multifaceted roles of integrins in breast cancer metastasis. J Mammary Gland Biol Neoplasia. 2007;12:135–42.

    Article  PubMed  Google Scholar 

  45. Gonzalez MA, et al. An immunohistochemical examination of the expression of E-cadherin, alpha- and beta/gamma-catenins, and alpha2- and beta1-integrins in invasive breast cancer. J Pathol. 1999;187(5):523–9.

    Article  PubMed  CAS  Google Scholar 

  46. Berry MG, Gui GP, Wells CA, Carpenter R. Integrin expression and survival in human breast cancer. Eur J Surg Oncol. 2004;30(5):484–9.

    Article  PubMed  CAS  Google Scholar 

  47. Diaz LK, et al. Beta4 integrin subunit gene expression correlates with tumor size and nuclear grade in early breast cancer. Mod Pathol. 2005;18(9):1165–75.

    Article  PubMed  CAS  Google Scholar 

  48. Lesniak D, et al. Beta1-integrin circumvents the antiproliferative effects of trastuzumab in human epidermal growth factor receptor-2-positive breast cancer. Cancer Res. 2009;69(22):8620–8.

    Article  PubMed  CAS  Google Scholar 

  49. Friedrichs K, et al. High expression level of alpha 6 integrin in human breast carcinoma is correlated with reduced survival. Cancer Res. 1995;55(4):901–6.

    PubMed  CAS  Google Scholar 

  50. Bergamaschi A, et al. Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome. J Pathol. 2008;214(3):357–67.

    Article  PubMed  CAS  Google Scholar 

  51. Gasparini G, et al. Vascular integrin alpha (v)beta 3: a new prognostic indicator in breast cancer. Clin Cancer Res. 1998;4(11):2625–34.

    PubMed  CAS  Google Scholar 

  52. Serre CM, Clezardin P, Frappart L, Boivin G, Delmas PD. Distribution of thrombospondin and integrin alpha V in DCIS, invasive ductal and lobular human breast carcinomas. Analysis by electron microscopy. Virchows Arch. 1995;427(4):365–72.

    Article  PubMed  CAS  Google Scholar 

  53. Lanzafame S, Emmanuele C, Torrisi A. Correlation of alpha 2 beta 1 integrin expression with histological type and hormonal receptor status in breast carcinomas. Pathol Res Pract. 1996;192(10):1031–8.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by the grant of The Ministry of Science of Republic of Croatia.

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Authors and Affiliations

  1. Department of Pathophysiology, Zagreb University Medical School, 10000, Zagreb, Croatia

    B. Petricevic

  2. Surgical Research Laboratories, Anna Spiegel Forschungsgebäude, Vienna University Medical School, Währinger Gürtel 18-20, 1090, Vienna, Austria

    B. Petricevic

  3. Department of Oncology, Clinical Hospital Center Zagreb, 10000, Zagreb, Croatia

    D. Vrbanec & T. Badovinac

  4. Department of Pathology and Cytology, Clinical Hospital Center Zagreb, Zagreb University Medical School, 10000, Zagreb, Croatia

    J. Jakic-Razumovic & I. Brcic

  5. Department of Traumatology III, Traumatology Clinic, Clinical Hospital Sestre milosrdince, 10000, Zagreb, Croatia

    D. Rabic

  6. Pediatric Department, General Hospital Zabok, 49210, Zabok, Croatia

    E. Ozimec

  7. Department of Cell Biology, University of Alabama, Birmingham, AL, 35209, USA

    V. Bali

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  1. B. Petricevic
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Correspondence to B. Petricevic.

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Petricevic, B., Vrbanec, D., Jakic-Razumovic, J. et al. Expression of Toll-like receptor 4 and beta 1 integrin in breast cancer. Med Oncol 29, 486–494 (2012). https://doi.org/10.1007/s12032-011-9885-0

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  • DOI: https://doi.org/10.1007/s12032-011-9885-0

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