Advertisement

Clinical & Experimental Metastasis

, Volume 35, Issue 8, pp 763–775 | Cite as

Dickkopf-1 (Dkk1) protein expression in breast cancer with special reference to bone metastases

  • Mariz Kasoha
  • Rainer M. Bohle
  • Anita Seibold
  • Christoph Gerlinger
  • Ingolf Juhasz-Böss
  • Erich-Franz Solomayer
Research Paper

Abstract

Dysregulation of the Wnt inhibitor dickkopf-1 protein (Dkk1) has been reported in a variety of cancers. In addition, it has been linked to the progression of malignant bone disease by impairing osteoblast activity. This study investigated serum- and tissue levels of Dkk1 in breast cancer patients with- or without bone metastases. Serum Dkk1 levels were measured by ELISA in 89 breast cancer patients and 86 healthy women. Tissue levels of Dkk1 and β-catenin, a major downstream component of Wnt transduction pathway, were tested with immunohistochemical staining in 143 different tissues, including adjacent non-tumoral breast tissues, primary breast tumours, lymph nodes metastases, and bone metastases. Serum levels of Dkk1 were significantly increased in breast cancer patients without metastases compared with healthy controls and even more increased in patients with bone metastases. Tissue expression of Dkk1 was positive in 70% of tested primary breast cancer tissues and demonstrated significant correlation with histological type and PR status. Less frequent expression of Dkk1 was found in lymph nodes metastases and bone metastases compared with adjacent non-tumoral breast tissues and primary breast tumours. Tissue expression of β-catenin was positive in the vast majority of all tested tissue types indicating activated Wnt/β-catenin signalling. Our results suggested that Wnt/β-catenin signalling in breast tumours and their secondary lymph nodes- and bone metastases is dysregulated and this could be related to aberrant Dkk1 expression levels. Hence, Dkk1 protein might provide insights into the continued development of novel comprehensive and therapeutic strategies for breast cancer and its bone metastases.

Keywords

Breast cancer Dickkopf-1 (Dkk1) Bone metastases β-Catenin Target therapy 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the local Ethic Committee of the Medical Association of the Saarland (Reference Number: 09/14). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Clevers H, Loh KM, Nusse R (2014) Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science.  https://doi.org/10.1126/science.1248012 CrossRefPubMedGoogle Scholar
  2. 2.
    Gao C, Chen YG (2010) Dishevelled: the hub of Wnt signaling. Cell Signal 22:717–727CrossRefGoogle Scholar
  3. 3.
    De A (2011) Wnt/Ca2+ signalling pathway: a brief overview. Acta Biochim Biophys Sin 43:745–756CrossRefGoogle Scholar
  4. 4.
    Clevers H (2006) Wnt/β-catenin signaling in development and disease. Cell 127:469–480CrossRefGoogle Scholar
  5. 5.
    Bovolenta P, Esteve P, Ruiz JM, Cisneros E, Lopez-Rios J (2008) Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease. J Cell Sci 121:737–746CrossRefGoogle Scholar
  6. 6.
    He X, Semenov M, Tamai K et al (2004) LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: arrows point the way. Development 131:1663–1677CrossRefGoogle Scholar
  7. 7.
    Mariz K, Ingolf JB, Daniel H, Teresa NJ, Erich-Franz S (2015) The Wnt inhibitor dickkopf-1: a link between breast cancer and bone metastases. Clin Exp Metastasis 32:857–866CrossRefGoogle Scholar
  8. 8.
    Gyu-Beom J, Ji-Young K, Sung-Dae C, Ki-Soo P, Ji-Youn J, Hwa-Yong L, In-Sun H, Jeong-Seok N (2015) Blockade of Wnt/β-catenin signaling suppresses BC metastasis by inhibiting CSC-like phenotype. Sci Rep.  https://doi.org/10.1038/srep12465 CrossRefGoogle Scholar
  9. 9.
    Merino VF, Cho S, Liang X, Park S, Jin K, Chen Q, Pan D, Zahnow CA, Rein AR, Sukumar S (2017) Inhibitors of STAT3, beta-catenin, and IGF-1R sensitize mouse PIK3CA mutant breast cancer to PI3K inhibitors. Mol Oncol 11:552–566CrossRefGoogle Scholar
  10. 10.
    Shen T, Zhang K, Siegal GP, Wei S (2016) Prognostic value of E-cadherin and beta-catenin in triple-negative breast cancer. Am J Clin Pathol 146:603–610CrossRefGoogle Scholar
  11. 11.
    Veeck J, Niederacher D, An H, Klopocki E et al (2006) Aberrant methylation of the Wnt antagonist SFRP1 in breast cancer is associated with unfavourable prognosis. Oncogene 25:3479–3488CrossRefGoogle Scholar
  12. 12.
    Xu WH, Liu ZB, Yang C et al (2012) Expression of dickkopf-1 and beta-catenin related to the prognosis of breast cancer patients with triple negative phenotype. PLoS ONE.  https://doi.org/10.1371/journal.pone.0037624 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Zhou SJ, Zhou SR, Yang XQ et al (2014) Serum Dickkopf-1 expression level positively correlates with a poor prognosis in breast cancer. Diagn Pathol.  https://doi.org/10.1186/s13000-014-0161-4 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Jemal A, Bray F, Center MM et al (2011) Global cancer statistics. CA Cancer J Clin 61:69–90CrossRefGoogle Scholar
  15. 15.
    Weigelt B, Peterse JL, van‘t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5:591–602. 2005CrossRefGoogle Scholar
  16. 16.
    Manders K, van de Poll-Franse LV, Creemers GJ et al (2006) Clinical management of women with metastatic breast cancer: a descriptive study according to age group. BMC Cancer 6:179CrossRefGoogle Scholar
  17. 17.
    Lipton A (2005) Management of bone metastases in breast cancer. Cur Treat Options Oncol 6:161–171CrossRefGoogle Scholar
  18. 18.
    Johnson RW, Merkel AR, Page JM, Ruppender NS, Guelcher SA, Sterling JA (2014) Wnt signaling induces gene expression of factors associated with bone destruction in lung and breast cancer. Clin Exp Metastasis 31:945–959CrossRefGoogle Scholar
  19. 19.
    Johnson RW, Mai PN, Susan SP et al (2010) TGF-β promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical hedgehog signaling. Cancer Res 71:822–831CrossRefGoogle Scholar
  20. 20.
    Gunn WG, Conley A, Deininger L et al (2006) A crosstalk between myeloma cells and marrow stromal cells stimulates production of DKK1 and interleukin-6: a potential role in the development of lytic bone disease and tumor progression in multiple myeloma. Stem Cells 24:986–991CrossRefGoogle Scholar
  21. 21.
    Heath DJ, Chantry AD, Buckle CH, Coulton L, Shaughnessy JD Jr, Evans HR, Snowden JA, Stover DR, Vanderkerken K, Croucher PI (2009) Inhibiting Dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. J Bone Miner Res 24:425–436CrossRefGoogle Scholar
  22. 22.
    Iyer SP, Beck JT, Stewart A et al (2014) A Phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events. Br J Haematol 167:366–375CrossRefGoogle Scholar
  23. 23.
    Durkee BY, Qian Y, Pollom EL, King MT, Dudley SA, Shaffer JL, Chang DT, Gibbs IC, Goldhaber-Fiebert JD, Horst KC (2016) Cost-effectiveness of pertuzumab in human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol 34:902–909CrossRefGoogle Scholar
  24. 24.
    Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8:138–140PubMedGoogle Scholar
  25. 25.
    Shao YC, Wei Y, Liu JF, Xu XY (2017) The role of Dickkopf family in cancers: from Bench to Bedside. Am J Cancer Res 7:1754–1768PubMedPubMedCentralGoogle Scholar
  26. 26.
    Kagey MH, He X (2017) Rationale for targeting the Wnt signalling modulator Dickkopf-1 for oncology. Br J Pharmacol.  https://doi.org/10.1111/bph.13894 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Mazon M, Masi D, Carreau M, Modulating (2016) Dickkopf-1: a strategy to monitor or treat cancer? Cancers (Basel).  https://doi.org/10.3390/cancers8070062 CrossRefGoogle Scholar
  28. 28.
    Liu Y, Tang W, Xie L et al (2014) Prognostic significance of dickkopf-1 overexpression in solid tumors: a meta-analysis. Tumour Biol 35:3145–3154CrossRefGoogle Scholar
  29. 29.
    González-Sancho JM, Aguilera O, García JM, Pendás-Franco N, Peña C, Cal S, García de Herreros A, Bonilla F, Muñoz A (2005) The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. Oncogene 24:1098–1103CrossRefGoogle Scholar
  30. 30.
    Sheng SL, Huang G, Yu B, Qin WX (2009) Clinical significance and prognostic value of serum Dickkopf-1 concentrations in patients with lung cancer. Clin Chem 55:1656–1664CrossRefGoogle Scholar
  31. 31.
    Fouad YM, Mohamed HI, Kamal EM, Rasek MA (2016) Clinical significance and diagnostic value of serum dickkopf-1 in patients with hepatocellular carcinoma. Scand J Gastroenterol 51:1133–1137CrossRefGoogle Scholar
  32. 32.
    Zhou Y, Liu F, Xu Q, Wang X (2010) Analysis of the expression profile of Dickkopf-1 gene in human glioma and the association with tumor malignancy. J Exp Clin Cancer Res 28:129–138Google Scholar
  33. 33.
    Liu JT, Guo WB, Sun JY (2017) Serum Dickkopf-1 acts as a new biomarker in human breast cancer. Minerva Med 108:334–340PubMedGoogle Scholar
  34. 34.
    Zhou XL, Qin XR, Zhang XD et al (2010) Downregulation of Dickkopf-1 is responsible for high proliferation of breast cancer cells via losing control of Wnt/beta-catenin signaling. Acta Pharmacol Sin 31:202–210CrossRefGoogle Scholar
  35. 35.
    Qiao L, Xu ZL, Zhao TJ, Ye LH, Zhang XD (2008) Dkk-1 secreted by mesenchymal stem cells inhibits growth of breast cancer cells via depression of Wnt signalling. Cancer Lett 269:67–77CrossRefGoogle Scholar
  36. 36.
    Mikheey AM, Mikheeva SA, Maxwell JP et al (2008) Dickkopf-1 mediated tumor suppression in human breast carcinoma cells. Breast Cancer Res Treat 112:263–273CrossRefGoogle Scholar
  37. 37.
    Forget MA, Turcotte S, Beauseigle D et al (2007) The Wnt pathway regulator DKK1 is preferentially expressed in hormone-resistant breast tumours and in some common cancer types. Br J Cancer 96:646–653CrossRefGoogle Scholar
  38. 38.
    Sato N, Yamabuki T, Takano A et al (2010) Wnt inhibitor Dickkopf-1 as a target for passive cancer immunotherapy. Cancer Res 70:5326–5336CrossRefGoogle Scholar
  39. 39.
    Kato M, Patel MS, Levasseur R et al (2002) Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol 157:303–314CrossRefGoogle Scholar
  40. 40.
    Glass DA 2nd, Bialek P, Ahn JD et al (2005) Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 8:751–764CrossRefGoogle Scholar
  41. 41.
    Christodoulides C, Scarda A, Granzotto M et al (2006) WNT10B mutations in human obesity. Diabetologia 49:678–684CrossRefGoogle Scholar
  42. 42.
    Cheng SL, Shao JS, Cai J, Sierra OL, Towler DA (2008) Msx2 exerts bone anabolism via canonical Wnt signaling. J Biol Chem 283:20505–20522CrossRefGoogle Scholar
  43. 43.
    Diarra D, Stolina M, Polzer K et al (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13:156–163CrossRefGoogle Scholar
  44. 44.
    Voorzanger-Rousselot N, Journe F, Doriath V et al (2009) Assessment of circulating Dickkopf-1 with a new two-site immunoassay in healthy subjects and women with breast cancer and bone metastases. Calcif Tissue Int 84:348–354CrossRefGoogle Scholar
  45. 45.
    Voorzanger-Rousselot N, Goehrig D, Journe F et al (2007) Increased Dickkopf-1 expression in breast cancer bone metastases. Br J Cancer 97:964–970CrossRefGoogle Scholar
  46. 46.
    Rachner TD, Göbel A, Thiele S (2014) Dickkopf-1 is regulated by the mevalonate pathway in breast cancer. Breast Cancer Res.  https://doi.org/10.1186/bcr3616 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Göbel A, Kuhlmann JD, Link T, Wimberger P, Browne AJ, Rauner M, Hofbauer LC, Rachner TD (2017) Adjuvant tamoxifen but not aromatase inhibitor therapy decreases serum levels of the Wnt inhibitor dickkopf-1 while not affecting sclerostin in breast cancer patients. Breast Cancer Res Treat 164:737–743CrossRefGoogle Scholar
  48. 48.
    Hideshima T, Mitsiades C, Tonon G et al (2007) Understanding multiple myloma pathogenesis in the bone marrow to identify new therapeutics targets. Nat Rev Cancer 7:585–595CrossRefGoogle Scholar
  49. 49.
    Qiang YW, Chen Y, Stephens O et al (2008) Myeloma derived Dickkopf-1 disrupts Wnt-regulated osteoprotegrin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma. Blood 112:196–207CrossRefGoogle Scholar
  50. 50.
    Bu G, Lu W, Liu CC, Selander K, Yoneda T, Hall C, Keller ET, Li Y (2008) Breast cancer-derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: implication for breast cancer osteolytic bone metastases. Int J Cancer 123:1034–1042CrossRefGoogle Scholar
  51. 51.
    Zhuang X, Zhang H, Li X, Li X, Cong M, Peng F, Yu J, Zhang X, Yang Q, Hu G (2017) Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1. Nat Cell Biol 19:1274–1285CrossRefGoogle Scholar
  52. 52.
    Tulac S, Overgaard MT, Hamilton AE, Jumbe NL, Suchanek E, Giudice LC (2006) Dickkopf-1, an inhibitor of Wnt signaling, is regulated by progesterone in human endometrial stromal cells. J Clin Endocrinol Metab 91:1453–1461CrossRefGoogle Scholar
  53. 53.
    Chen W, Zahng UW, Li Y, Zahng JW, Zahng T, Fu BS, Zahng Q, Jiang N (2016) Constitutive expression of Wnt/β-catenin target genes promotes proliferation and invasion of liver cancer stem cells. Mol Med Rep 13:3466–3474CrossRefGoogle Scholar
  54. 54.
    Acar M, Çora T, Toy H, Acar H (2012) Analysis of promoter methylation of Dickkopf1 (DKK1) gene in breast cancer. Turk J Med Sci 42:1379–1387Google Scholar
  55. 55.
    Dolled-Filhart M, McCabe A, Giltnane J, Cregger M, Camp RL, Rimm DL (2006) Quantitative in situ analysis of beta-catenin expression in breast cancer shows decreased expression is associated with poor outcome. Cancer Res 66:5487–5494CrossRefGoogle Scholar
  56. 56.
    Eads J, El-Khoueiry A, Manji G et al (2016) Phase I study of DKN-01 (D), an anti-DKK1 monoclonal antibody, in combination with gemcitabine (G) and cisplatin (C) in patients (pts) with advanced biliary cancer (ABC). Ann Oncol 27(suppl_6):698CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Department of Gynecology, Obstetrics and Reproductive MedicineUniversity Medical School of SaarlandHomburgGermany
  2. 2.Institute of General and Special PathologyUniversity Medical School of SaarlandHomburgGermany

Personalised recommendations