Breast cancer-derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: implication for breast cancer osteolytic bone metastases.

• Abstract: Most breast cancer metastases in bone form osteolytic lesions, but the mechanisms of tumor-induced bone resorption and destruction are not fully understood. Although it is well recognized that Wnt/beta-catenin signaling is important for breast cancer tumorigenesis, the role of this pathway in breast cancer bone metastasis is unclear. Dickkopf1 (Dkk1) is a secreted Wnt/beta-catenin antagonist. In the present study, we demonstrated that activation of Wnt/beta-catenin signaling enhanced Dkk1 expression in breast cancer cells and that Dkk1 overexpression is a frequent event in breast cancer. We also found that human breast cancer cell lines that preferentially form osteolytic bone metastases exhibited increased levels of Wnt/beta-catenin signaling and Dkk1 expression. Moreover, we showed that breast cancer cell-produced Dkk1 blocked Wnt3A-induced osteoblastic differentiation and osteoprotegerin (OPG) expression of osteoblast precursor C2C12 cells and that these effects could be neutralized by a specific anti-Dkk1 antibody. In addition, we found that breast cancer cell conditioned media were able to block Wnt3A-induced NF-kappaB ligand reduction in C2C12 cells. Finally, we demonstrated that conditioned media from breast cancer cells in which Dkk1 expression had been silenced via RNAi were unable to block Wnt3A-induced C2C12 osteoblastic differentiation and OPG expression. Taken together, these results suggest that breast cancer-produced Dkk1 may be an important mechanistic link between primary breast tumors and secondary osteolytic bone metastases.
• Authors: Guojun Bu, Wenyan Lu, Chia-Chen Liu, Katri Selander, Toshiyuki Yoneda, Christopher Hall, Evan T Keller, Yonghe Li (Affiliation: Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.)
• Journal: International journal of cancer. Journal international du cancer (Int J Cancer) Vol. 123 Issue 5 Pg. 1034-42 (Sep 1 2008) ISSN: 1097-0215 [Electronic] United States
• PMID: 18546262 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DKK1 protein, human
• Intercellular Signaling Peptides and Proteins
• NF-kappa B
• Osteoprotegerin
• RANK Ligand
• TNFSF11 protein, human
• Wnt Proteins
• Wnt-3 protein
• beta Catenin

Topics

• Bone Neoplasms (metabolism, secondary)
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Intercellular Signaling Peptides and Proteins (metabolism)
• NF-kappa B (metabolism)
• Osteoblasts (metabolism, pathology)
• Osteolysis
• Osteoprotegerin (metabolism)
• RANK Ligand (metabolism)
• Up-Regulation
• Wnt Proteins (metabolism)
• beta Catenin (metabolism)