/project 8

T. Rachner and M. Rauner, Dresden

Dickkopf-1 as determinant of the bone metastatic phenotype in breast cancer

Dickkopf-1 (DKK-1) is a Wnt inhibitor and associated with the development of bone lesions in multiple myeloma by inhibiting osteoblast function. We have previously shown that DKK-1 is highly expressed in breast cancer tissue and elevated in the serum of affected patients. As part of a physician-scientist (Gerok) project, we identified elevated DKK-1 expression in prostate cancer tissue and significantly better survival in patients with prostate cancer, who had low levels of DKK-1 at the time of diagnosis. In vitro, breast and prostate cancer cell lines with high levels of DKK-1 inhibit osteoblast differentiation, which can be reversed by blocking DKK-1. Based on these results, we hypothesize that DKK-1 is a critical determinant of the formation of skeletal metastases and is a suitable prognostic marker for breast cancer survival and a potential therapeutic target in osteotropic malignancies.

Our specific aims within this project are to:

(I) assess the prognostic value of DKK-1 using a prognostic breast cancer tissue array (from the NCI) and serum analyses of a well-characterized cohort of breast cancer patients;

(II) analyze the role of DKK-1 in the mutual interaction of cancer and bone cells (MSC, osteoclasts) in vitro by modulating DKK-1 using RNAi and overexpression constructs;

(III) determine the therapeutic potential of DKK-1 in murine models of breast cancer (subcutaneous, intratibial and intracardiac tumor models) by stably over-expressing and inhibiting DKK-1 in breast cancer and melanoma cell lines, and by inhibiting DKK-1 using a monoclonal antibody;

(IV) clarify the role of non-tumor derived DKK-1 in cancer progression using mice with a conditional global deletion of DKK-1 after skeletal development or a deletion of DKK-1 specifically in osteoblasts. Tumor growth and bone destruction will be determined using micro-CT, luminescence imaging, and histology. Furthermore the bone anabolic effects of DKK-1 inhibition will be comprehensively studied using bone histomorphometry, serum bone remodeling markers and imaging. These studies will help to clarify the molecular mechanisms and therapeutic potential of modifying DKK-1 signaling in bone metastasis.
 


 

Dr. med. Tilman D. Rachner works as physician at the Department of Endocrinology, Diabetes and Bone disorders at the University Hospital Dresden and is a Junior Group Leader in the field of osteooncology at the Faculty of Medicine at TU Dresden. Since 2013, Tilman has been involved in the SKELMET project as a Gerok fellow. He studied Medicine at the Philipps University of Marburg.


 

Dr. scient. med. Martina Rauner is a Junior Group Leader in the field of osteoimmunology at the Faculty of Medicine at TU Dresden. Martina has been involved in the SKELMET research group as a scientific co-worker in project 3 from the very beginning. She’s Austrian and obtained her PhD from the Medical University of Vienna in 2008.

 
Project-related list of publications

Browne AJ, Göbel A, Thiele S, Hofbauer LC, Rauner M, Rachner TD. p38 MAPK regulates the Wnt inhibitor Dickkopf-1 in osteotropic prostate cancer cells. Cell Death Dis. 2016;7:e2119. 
 
Göbel A, Thiele S, Browne AJ, Rauner M, Zinna VM, Hofbauer LC, Rachner TD. Combined inhibition of the mevalonate pathway with statins and zoledronic acid potentiates their anti-tumor effects in human breast cancer cells. Cancer Lett. 2016;375:162-71.
 
Rachner TD, Rauner M. RANKL/OPG in Breast Cancer - Extending Its Territory to BRCA Mutation Carriers. EBioMedicine. 2015;2:1270-1.
 
Thiele S, Rachner TD, Rauner M, Hofbauer LC. WNT5A and Its Receptors in the Bone-Cancer Dialogue. J Bone Miner Res. 2016;31:1488-96.
 
Rachner TD, Wimberger P, Hofbauer LC. Prospects of adjuvant RANKL inhibition in breast cancer? Cell Death Dis. 2015;6:e1982. 
 
Göbel A, Browne AJ, Thiele S, Rauner M, Hofbauer LC, Rachner TD. Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins. Breast Cancer Res Treat. 2015;154:623-31.
 
Rachner TD, Göbel A, Browne A, Hötzel J, Rauner M, Hofbauer LC. P38 regulates the Wnt inhibitor Dickkopf-1 in breast cancer. Biochem Biophys Res Commun. 2015;466:728-32.
 
Rachner TD, Jakob F, Hofbauer LC. Cancer-targeted therapies and radiopharmaceuticals. Bonekey Rep. 2015;4:707. Review.
 
Todenhöfer T, Stenzl A, Hofbauer LC, Rachner TD. Targeting bone metabolism in patients with advanced prostate cancer: current options and controversies. Int J  Endocrinol. 2015;2015:838202. Review.
 
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. High serum levels of Dickkopf-1 are associated with a poor prognosis in prostate cancer patients. BMC Cancer. 2014;14:649.

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. Dickkopf-1 is regulated by the mevalonate pathway in breast cancer. Breast Cancer Res 2014;16:20.

Rachner TD, Göbel A, Benad-Mehner P, Hofbauer LC, Rauner M. Dickkopf-1 as a mediator and novel target in malignant bone disease. Cancer Lett 2014;346:172-7.

Hofbauer LC, Rachner TD, Coleman RE, Jakob F. Endocrine aspects of bone metastases. Lancet Diabetes Endocrinol 2014;2:500-12.

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

Benad-Mehner P, Thiele S, Rachner TD, Göbel A, Rauner M, Hofbauer LC. Targeting syndecan-1 in breast cancer inhibits osteoclast functions through up-regulation of osteoprotegerin. J Bone Oncol 2014;3:18-24.

Rauner M, Stein N, Winzer M, Goettsch C, Zwerina J, Schett G, Distler JH, Albers J, Schulze J, Schinke T, Bornhäuser M, Platzbecker U, Hofbauer LC. WNT5A is induced by inflammatory mediators in bone marrow stromal cells and regulates cytokine and chemokine production. J Bone Miner Res 2012;27:575-85.

Benad P, Rauner M, Rachner TD, Hofbauer LC. The anti-progestin RU-486 inhibits viability of MCF-7 breast cancer cells by suppressing WNT1. Cancer Lett 2011;312:101-8.

Thiele S, Rauner M, Goettsch C, Rachner TD, Benad P, Fuessel S, Erdmann K, Hamann C, Baretton GB, Wirth MP, Jakob F, Hofbauer LC. Expression profile of WNT molecules in prostate cancer and its regulation by aminobisphosphonates. J Cell Biochem 2011;112:1593-600.

Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet 2011;377:1276-87.

Technische Universitt Dresden    Christian-Albrechts-Universitt zu Kiel    Julius-Maximilians-Universitt Wrzburg
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