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MEK-dependent IL-8 induction regulates the invasiveness of triple-negative breast cancer cells

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Tumor Biology

Abstract

Interleukin-8 (IL-8) serves as a prognostic marker for breast cancer, and its expression level correlates with metastatic breast cancer and poor prognosis. Here, we investigated the levels of IL-8 expression in a variety of breast cancer cells and the regulatory mechanism of IL-8 in triple-negative breast cancer (TNBC) cells. Our results showed that IL-8 expression correlated positively with overall survival in basal-type breast cancer patients. The levels of IL-8 mRNA expression and protein secretion were significantly increased in TNBC cells compared with non-TNBC cells. In addition, the invasiveness of the TNBC cells was dramatically increased by IL-8 treatment and then augmented invasion-related proteins such as matrix metalloproteinase (MMP)-2 or MMP-9. We observed that elevated IL-8 mRNA expression and protein secretion were suppressed by a specific MEK1/2 inhibitor, UO126. In contrast, the overexpression of constitutively active MEK significantly increased the level of IL-8 mRNA expression in BT474 non-TNBC cells. Finally, we investigated the effect of UO126 on the tumorigenecity of TNBC cells. Our results showed that anchorage-independent growth, cell invasion, and cell migration were also decreased by UO126 in TNBC cells. As such, we demonstrated that IL-8 expression is regulated through MEK/ERK-dependent pathways in TNBC cells. A diversity of MEK blockers, including UO126, may be promising for treating TNBC patients.

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References

  1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.

    Article  PubMed  Google Scholar 

  2. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295:2492–502. doi:10.1001/jama.295.21.2492.

    Article  CAS  PubMed  Google Scholar 

  3. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13:4429–34. doi:10.1158/1078-0432.CCR-06-3045.

    Article  PubMed  Google Scholar 

  4. Thike AA, Cheok PY, Jara-Lazaro AR, Tan B, Tan P, Tan PH. Triple-negative breast cancer: clinicopathological characteristics and relationship with basal-like breast cancer. Mod Pathol. 2010;23:123–33. doi:10.1038/modpathol.2009.145.

    Article  CAS  PubMed  Google Scholar 

  5. Lin NU, Claus E, Sohl J, Razzak AR, Arnaout A, Winer EP. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer Lett. 2008;113:2638–45. doi:10.1002/cncr.23930.

    Article  Google Scholar 

  6. Otvos Jr L, Surmacz E. Targeting the leptin receptor: a potential new mode of treatment for breast cancer. Expert Rev Anticancer Ther. 2011;11:1147–50. doi:10.1586/era.11.109.

    Article  CAS  PubMed  Google Scholar 

  7. Waugh DJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res. 2008;14:6735–41. doi:10.1158/1078-0432.CCR-07-4843.

    Article  CAS  PubMed  Google Scholar 

  8. Green AR, Green VL, White MC, Speirs V. 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. 1997;72:937–41.

    Article  CAS  PubMed  Google Scholar 

  9. Ivarsson K, Ekerydh A, Fyhr IM, Janson PO, Brannstrom M. Upregulation of interleukin-8 and polarized epithelial expression of interleukin-8 receptor A in ovarian carcinomas. Acta Obstet Gynecol Scand. 2000;79:777–84.

    CAS  PubMed  Google Scholar 

  10. Singh RK, Gutman M, Radinsky R, Bucana CD, Fidler IJ. Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Res. 1994;54:3242–7.

    CAS  PubMed  Google Scholar 

  11. Miller LJ, Kurtzman SH, Wang Y, Anderson KH, Lindquist RR, Kreutzer DL. Expression of interleukin-8 receptors on tumor cells and vascular endothelial cells in human breast cancer tissue. Anticancer Res. 1998;18:77–81.

    CAS  PubMed  Google Scholar 

  12. Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M. Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes Dev. 1999;13:1297–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lee LF, Li G, Templeton DJ, Ting JP. Paclitaxel (Taxol)-induced gene expression and cell death are both mediated by the activation of c-Jun NH2-terminal kinase (JNK/SAPK). J Biol Chem. 1998;273:28253–60.

    Article  CAS  PubMed  Google Scholar 

  14. Scherle PA, Jones EA, Favata MF, Daulerio AJ, Covington MB, Nurnberg SA, et al. Inhibition of map kinase kinase prevents cytokine and prostaglandin E2 production in lipopolysaccharide-stimulated monocytes. J Immunol. 1998;161:5681–6.

    CAS  PubMed  Google Scholar 

  15. Itoh Y, Joh T, Tanida S, Sasaki M, Kataoka H, Itoh K, et al. IL-8 promotes cell proliferation and migration through metalloproteinase-cleavage proHB-EGF in human colon carcinoma cells. Cytokine+. 2005;29:275–82. doi:10.1016/j.cyto.2004.11.005.

    CAS  PubMed  Google Scholar 

  16. Krzystek-Korpacka M, Matusiewicz M, Diakowska D, Grabowski K, Blachut K, Konieczny D, et al. Elevation of circulating interleukin-8 is related to lymph node and distant metastases in esophageal squamous cell carcinomas—implication for clinical evaluation of cancer patient. Cytokine+. 2008;41:232–9. doi:10.1016/j.cyto.2007.11.011.

    CAS  PubMed  Google Scholar 

  17. Hartman ZC, Poage GM, den Hollander P, Tsimelzon A, Hill J, Panupinthu N, et al. Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8. Cancer Res. 2013;73:3470–80. doi:10.1158/0008-5472.CAN-12-4524-T.

    Article  CAS  PubMed  Google Scholar 

  18. Wang Y, Xu RC, Zhang XL, Niu XL, Qu Y, Li LZ, et al. Interleukin-8 secretion by ovarian cancer cells increases anchorage-independent growth, proliferation, angiogenic potential, adhesion and invasion. Cytokine+. 2012;59:145–55. doi:10.1016/j.cyto.2012.04.013.

    CAS  PubMed  Google Scholar 

  19. Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123:725–31. doi:10.1007/s10549-009-0674-9.

    Article  PubMed  Google Scholar 

  20. Benoy IH, Salgado R, Van Dam P, Geboers K, Van Marck E, Scharpe S, et al. Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival. Clin Cancer Res. 2004;10:7157–62. doi:10.1158/1078-0432.CCR-04-0812.

    Article  CAS  PubMed  Google Scholar 

  21. Derin D, Soydinc HO, Guney N, Tas F, Camlica H, Duranyildiz D, et al. Serum IL-8 and IL-12 levels in breast cancer. Med Oncol. 2007;24:163–8.

    Article  CAS  PubMed  Google Scholar 

  22. Chen Y, Chen L, Li JY, Mukaida N, Wang Q, Yang C, et al. ERbeta and PEA3 co-activate IL-8 expression and promote the invasion of breast cancer cells. Cancer Biol Ther. 2011;11:497–511.

    Article  CAS  PubMed  Google Scholar 

  23. Lin Y, Huang R, Chen L, Li S, Shi Q, Jordan C, et al. Identification of interleukin-8 as estrogen receptor-regulated factor involved in breast cancer invasion and angiogenesis by protein arrays. Int J Cancer. 2004;109:507–15. doi:10.1002/ijc.11724.

    Article  CAS  PubMed  Google Scholar 

  24. Bauvois B. New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. Biochim Biophys Acta. 1825;2012:29–36. doi:10.1016/j.bbcan.2011.10.001.

    Google Scholar 

  25. Inoue K, Slaton JW, Eve BY, Kim SJ, Perrotte P, Balbay MD, et al. Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer. Clin Cancer Res. 2000;6:2104–19.

    CAS  PubMed  Google Scholar 

  26. Kim S, Lee J, Jeon M, Nam SJ, Lee JE. Elevated TGF-beta1 and -beta2 expression accelerates the epithelial to mesenchymal transition in triple-negative breast cancer cells. Cytokine+. 2015;75:151–8. doi:10.1016/j.cyto.2015.05.020.

    CAS  PubMed  Google Scholar 

  27. Natarajan R, Gupta S, Fisher BJ, Ghosh S, Fowler 3rd AA. Nitric oxide suppresses IL-8 transcription by inhibiting c-Jun N-terminal kinase-induced AP-1 activation. Exp Cell Res. 2001;266:203–12. doi:10.1006/excr.2001.5218.

    Article  CAS  PubMed  Google Scholar 

  28. Wu GD, Lai EJ, Huang N, Wen X. Oct-1 and CCAAT/enhancer-binding protein (C/EBP) bind to overlapping elements within the interleukin-8 promoter. The role of Oct-1 as a transcriptional repressor. J Biol Chem. 1997;272:2396–403.

    Article  CAS  PubMed  Google Scholar 

  29. Karin M, Liu Z, Zandi E. AP-1 function and regulation. Curr Opin Cell Biol. 1997;9:240–6.

    Article  CAS  PubMed  Google Scholar 

  30. Suzuki M, Tetsuka T, Yoshida S, Watanabe N, Kobayashi M, Matsui N, et al. The role of p38 mitogen-activated protein kinase in IL-6 and IL-8 production from the TNF-alpha- or IL-1beta-stimulated rheumatoid synovial fibroblasts. FEBS Lett. 2000;465:23–7.

    Article  CAS  PubMed  Google Scholar 

  31. Penson RT, Kronish K, Duan Z, Feller AJ, Stark P, Cook SE, et al. Cytokines IL-1beta, IL-2, IL-6, IL-8, MCP-1, GM-CSF and TNFalpha in patients with epithelial ovarian cancer and their relationship to treatment with paclitaxel. Int J Gynecol Cancer. 2000;10:33–41.

    Article  PubMed  Google Scholar 

  32. Bhola NE, Balko JM, Dugger TC, Kuba MG, Sanchez V, Sanders M, et al. TGF-beta inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest. 2013;123:1348–58. doi:10.1172/JCI65416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) and funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3418), and by a Samsung Biomedical Research Institute grant (SMX1131701).

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Authors and Affiliations

  1. Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, South Korea

    Sangmin Kim, Jeongmin Lee, Myeongjin Jeon, Jeong Eon Lee & Seok Jin Nam

  2. Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, South Korea

    Myeongjin Jeon & Jeong Eon Lee

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  1. Sangmin Kim
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  2. Jeongmin Lee
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Correspondence to Sangmin Kim or Seok Jin Nam.

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Supplement 1

The co-relation between IL-8 expression and relapse-free survival in luminal B- and HER2-type breast cancer patients. We analyzed the clinical value of IL-8 in luminal B- and HER2-type breast cancer patients using a public database [Kaplan–Meier plotter database (http://kmplot.com/breast)]. (A) Relapse-free survival of luminal B type breast cancer patients. (B) Relapse-free survival of HER2 type breast cancer patients. Lum: Luminal. (GIF 10 kb)

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Supplement 2

IL-8-induced cell invasion is suppressed by SB225002 in MDA-MB231 cells. (A) We analyzed the levels of MEK and ERK phosphorylation using whole cell lysates in BT474 and MDA-MB231 cells. The levels of phospho-MEK, phospho-ERK, and β-actin expression were analyzed by western blotting. (B) MDA-MB231 cells was pretreated with 10 μM SB225002 for 30 min and then treated with 20 ng/ml IL-8 for 16 h. The cells on the bottom side of the filter were fixed and stained. Cell morphology was analyzed using a CK40 inverted microscope. These results are representative of three independent experiments. Con: control, SB: SB225002. (GIF 14 kb)

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Kim, S., Lee, J., Jeon, M. et al. MEK-dependent IL-8 induction regulates the invasiveness of triple-negative breast cancer cells. Tumor Biol. 37, 4991–4999 (2016). https://doi.org/10.1007/s13277-015-4345-7

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  • DOI: https://doi.org/10.1007/s13277-015-4345-7

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