Skip to main content

Advertisement

SpringerLink
Log in

Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins

  • Brief Report
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The Wnt-inhibitor dickkopf-1 (DKK-1) promotes cancer-induced osteolytic bone lesions by direct inhibition of osteoblast differentiation and indirect activation of osteoclasts. DKK-1 is highly expressed in human breast cancer cells and can be suppressed by inhibitors of the mevalonate pathway such as statins and amino-bisphosphonates. However, supraphysiological concentrations are required to suppress DKK-1. We show that a sequential mevalonate pathway blockade using statins and amino-bisphosphonates suppresses DKK-1 more significantly than the individual agents alone. Thus, the reduction of the DKK-1 expression and secretion in the human osteotropic tumor cell lines MDA-MB-231, MDA-MET, and MDA-BONE by zoledronic acid was potentiated by the combination with low concentrations of statins (atorvastatin, simvastatin, and rosuvastatin) by up to 75 % (p < 0.05). The specific rescue of prenylation using farnesyl pyrophosphate or geranylgeranyl pyrophosphate revealed that these effects were mediated by suppressed geranylgeranylation rather than by suppressed farnesylation. Moreover, combining low concentrations of statins (1 µM atorvastatin or 0.25 µM simvastatin) and zoledronic acid at low concentrations resulted in an at least 50 % reversal of breast cancer-derived DKK-1-mediated inhibition of osteogenic markers in C2C12 cells (p < 0.05). Finally, the intratumoral injection of atorvastatin and zoledronic acid in as subcutaneous MDA-MB-231 mouse model reduced the serum level of human DKK-1 by 25 % compared to untreated mice. Hence our study reveals that a sequential mevalonate pathway blockade allows for the combined use of low concentration of statins and amino-bisphosphonates. This combination still significantly suppresses breast cancer-derived DKK-1 to levels where it can no longer inhibit Wnt-mediated osteoblast differentiation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Mundy GR (2002) Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2:584–593

    Article  CAS  PubMed  Google Scholar 

  2. Hofbauer LC, Rachner TD, Coleman RE, Jakob F (2014) Endocrine aspects of bone metastases. Lancet Diabetes Endocrinol 2(June):500–512

    Article  CAS  PubMed  Google Scholar 

  3. Rachner TD, Göbel A, Benad-Mehner P, Hofbauer LC, Rauner M (2014) Dickkopf-1 as a mediator and novel target in malignant bone disease. Cancer Lett 346:172–177

    Article  CAS  PubMed  Google Scholar 

  4. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD (2003) The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349:2483–2494

    Article  CAS  PubMed  Google Scholar 

  5. Hall CL, Bafico A, Dai J, Aaronson SA, Keller ET (2005) Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res 65:7554–7560

    CAS  PubMed  Google Scholar 

  6. Bu G, Lu W, Liu CC, Selander K, Yoneda T, Hall C, Keller ET, Li Y (2007) Breast cancer-derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: Implication for breast cancer osteolytic bone metastases. Int J Cancer 2008(123):1034–1042

    Google Scholar 

  7. Forget M, Turcotte S, Beauseigle D, Godin-Ethier J, Pelletier S, Martin J, Tanguay S, Lapointe R (2007) The Wnt pathway regulator DKK1 is preferentially expressed in hormone-resistant breast tumours and in some common cancer types. Br J Cancer 96:646–653

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Costa L (2007) Bisphosphonates: reducing the risk of skeletal complications from bone metastasis. Breast 16:16–20

    Article  Google Scholar 

  9. Thurnher M, Nussbaumer O, Gruenbacher G (2012) Novel aspects of mevalonate pathway inhibitors as antitumor agents. Clin Cancer Res 18:3524–3531

    Article  CAS  PubMed  Google Scholar 

  10. Demierre M-F, Demierre M-F, Higgins PDR, Higgins PDR, Gruber SB, Gruber SB, Hawk E, Hawk E, Lippman SM, Lippman SM (2005) Statins and cancer prevention. Nat Rev Cancer 5(December):930–942

    Article  CAS  PubMed  Google Scholar 

  11. Rachner TD, Göbel A, Thiele S, Rauner M, Benad-Mehner P, Hadji P, Bauer T, Muders MH, Baretton GB, Jakob F, Ebert R, Bornhäuser M, Schem C, Hofbauer LC (2014) Dickkopf-1 is regulated by the mevalonate pathway in breast cancer. Breast Cancer Res 16:R20

    Article  PubMed Central  PubMed  Google Scholar 

  12. Berndt N, Sebti SM (2011) Measurement of protein farnesylation and geranylgeranylation in vitro, in cultured cells and in biopsies, and the effects of prenyl transferase inhibitors. Nat Protoc 6:1775–1791

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Yoneda T, Williams PJ, Hiraga T, Niewolna M, Nishimura R (2001) A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. J Bone Miner Res 16:1486–1495

    Article  CAS  PubMed  Google Scholar 

  14. Bendre MS, Gaddy-Kurten D, Mon-Foote T, Akel NS, Skinner RA, Nicholas RW, Suva LJ (2002) Expression of interleukin 8 and not parathyroid hormone-related protein by human breast cancer cells correlates with bone metastasis in vivo. Cancer Res 62:5571–5579

    CAS  PubMed  Google Scholar 

  15. Rachner TD, Thiele S, Göbel A, Browne A, Fuessel S, Erdmann K, Wirth MP, Fröhner M, Todenhöfer T, Muders MH, Kieslinger M, Rauner M, Hofbauer LC (2014) High serum levels of Dickkopf-1 are associated with a poor prognosis in prostate cancer patients. BMC Cancer 14:649

    Article  PubMed Central  PubMed  Google Scholar 

  16. Wilke M, Göbel A, Rauner M, Benad-Mehner P, Schütze N, Füssel S, Hadji P, Hofbauer LC, Rachner TD (2014) Zoledronic acid and atorvastatin inhibit αvβ3-mediated adhesion of breast cancer cells. J Bone Oncol 3:10–17

    Article  Google Scholar 

  17. Ageberg M, Rydström K, Lindén O, Linderoth J, Jerkeman M, Drott K (2011) Inhibition of geranylgeranylation mediates sensitivity to CHOP-induced cell death of DLBCL cell lines. Exp Cell Res 317:1179–1191

    Article  CAS  PubMed  Google Scholar 

  18. Michailidou M, Brown HK, Lefley DV, Evans A, Cross SS, Coleman RE, Brown NJ, Holen I (2010) Microvascular endothelial cell responses in vitro and in vivo: modulation by zoledronic acid and paclitaxel? J Vasc Res 47:481–493

    Article  CAS  PubMed  Google Scholar 

  19. Wakchoure S, Merrell MA, Aldrich W, Millender-Swain T, Harris KW, Triozzi P, Selander KS (2006) Bisphosphonates inhibit the growth of mesothelioma cells in vitro and in vivo. Clin Cancer Res 12:2862–2868

    Article  CAS  PubMed  Google Scholar 

  20. Winter-Vann AM, Casey PJ (2005) Post-prenylation-processing enzymes as new targets in oncogenesis. Nat Rev Cancer 5(May):405–412

    Article  CAS  PubMed  Google Scholar 

  21. Mandal CC, Ghosh-Choudhury N, Yoneda T, Choudhury GG, Ghosh-Choudhury N (2011) Simvastatin prevents skeletal metastasis of breast cancer by an antagonistic interplay between p53 and CD44. J Biol Chem 286:11314–11327

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Chan KKW, Oza AM, Siu LL (2003) The statins as anticancer agents. Clin Cancer Res 9(1):10–19

    CAS  PubMed  Google Scholar 

  23. Clézardin P (2012) Mechanisms of action of bisphosphonates in oncology: a scientific concept evolving from antiresorptive to anticancer activities. Bonekey Rep 2013(2):267

    Google Scholar 

  24. Voorzanger-Rousselot N, Goehrig D, Journe F, Doriath V, Body JJ, Clézardin P, Garnero P (2007) Increased Dickkopf-1 expression in breast cancer bone metastases. Br J Cancer 97:964–970

    PubMed Central  CAS  PubMed  Google Scholar 

  25. Fulciniti M, Tassone P, Hideshima T, Vallet S, Nanjappa P, Ettenberg SA, Shen Z, Patel N, Tai YT, Chauhan D, Mitsiades C, Prabhala R, Raje N, Anderson KC, Stover DR, Munshi NC (2009) Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood 114:371–379

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Iyer SP, Beck JT, Stewart AK, Shah J, Kelly KR, Isaacs R, Bilic S, Sen S, Munshi NC (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 167:366–375

    Article  CAS  PubMed  Google Scholar 

  27. Rachner TD, Göbel A, Junker M, Hötzel J, Benad-Mehner P, Hadji P, Hofbauer LC (2013) Regulation of VEGF by mevalonate pathway inhibition in breast cancer. J Bone Oncol 2:110–115

    Article  Google Scholar 

  28. Van de Donk NWCJ, Kamphuis MMJ, Van Kessel B, Lokhorst HM, Bloem AC (2003) Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels. Blood 102:3354–3362

    Article  PubMed  Google Scholar 

  29. Van De Donk NWCJ, Schotte D, Kamphuis MMJ, Van Marion AMW, Van Kessel B, Bloem AC, Lokhorst HM (2003) Protein geranylgeranylation is critical for the regulation of survival and proliferation of lymphoma tumor cells. Clin Cancer Res 9:5735–5748

    PubMed  Google Scholar 

  30. Zhu Y, Casey PJ, Kumar AP, Pervaiz S (2013) Deciphering the signaling networks underlying simvastatin-induced apoptosis in human cancer cells: evidence for non-canonical activation of RhoA and Rac1 GTPases. Cell Death Dis 4:e568

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Gronich N, Rennert G (2013) Beyond aspirin-cancer prevention with statins, metformin and bisphosphonates. Nat Rev Clin Oncol 10:625–642

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Ms. Josefa Hötzel and Ms. Bärbel Zeiler for their excellent technical assistance and Ms. Theresa Reiche for her secretarial assistance. The work was funded by the Deutsche Forschungsgemeinschaft to Dr. Rachner (RA 2151/2-1 and 3-1) and to Dr. Hofbauer (HO 1875/15-1 and 16-1) as part of the DFG Research group SKELMET.

Author Contributions

Study Design: AG and TDR. Study conduct: AG and AJB. Data collection: AG, AJB, and ST. Data analysis: AG, MR, ST and TDR. Data interpretation: AG, AJB, ST, MR, LCH, and TDR. Drafting Manuscript: AG and TDR. Revising manuscript content: AG, AJB, ST, MR, LCH, and TDR. Approving final version of manuscript: AG, AJB, ST, MR, LCH, and TDR. AG takes responsibility of the integrity of the data analysis.

Author information

Authors and Affiliations

  1. Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany

    Andy Göbel, Andrew J. Browne, Stefanie Thiele, Martina Rauner, Lorenz C. Hofbauer & Tilman D. Rachner

  2. Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany

    Lorenz C. Hofbauer

Authors
  1. Andy Göbel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew J. Browne
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefanie Thiele
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martina Rauner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lorenz C. Hofbauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tilman D. Rachner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tilman D. Rachner.

Ethics declarations

Conflict of Interest

The authors have received grants or honorarium for advisory boards or lectures to the individual or the institution by Amgen (LCH, TDR), Novartis (LCH, TDR), and Merck (LCH, TDR)). AG, AJB, ST, and MR declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Göbel, A., Browne, A.J., Thiele, S. et al. Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins. Breast Cancer Res Treat 154, 623–631 (2015). https://doi.org/10.1007/s10549-015-3624-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-015-3624-8

Keywords

Search

Navigation