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Although it is well recognized that Wnt\/\u03b2\u2010catenin 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\/\u03b2\u2010catenin antagonist. In the present study, we demonstrated that activation of Wnt\/\u03b2\u2010catenin 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\/\u03b2\u2010catenin signaling and Dkk1 expression. Moreover, we showed that breast cancer cell\u2010produced Dkk1 blocked Wnt3A\u2010induced osteoblastic differentiation and osteoprotegerin (OPG) expression of osteoblast precursor C2C12 cells and that these effects could be neutralized by a specific anti\u2010Dkk1 antibody. In addition, we found that breast cancer cell conditioned media were able to block Wnt3A\u2010induced NF\u2010kappaB ligand reduction in C2C12 cells. Finally, we demonstrated that conditioned media from breast cancer cells in which Dkk1 expression had been silenced <jats:italic>via<\/jats:italic> RNAi were unable to block Wnt3A\u2010induced C2C12 osteoblastic differentiation and OPG expression. Taken together, these results suggest that breast cancer\u2010produced Dkk1 may be an important mechanistic link between primary breast tumors and secondary osteolytic bone metastases. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.23625","type":"journal-article","created":{"date-parts":[[2008,6,10]],"date-time":"2008-06-10T19:47:47Z","timestamp":1213127267000},"page":"1034-1042","source":"Crossref","is-referenced-by-count":112,"title":["Breast cancer\u2010derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: Implication for breast cancer osteolytic bone 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