Dickkopf‐1 expression increases early in prostate cancer development and decreases during progression from primary tumor to metastasis

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Abstract
BACKGROUND Prostate cancer (PCa) frequently metastasizes to the bone and induces osteoblastic lesions. We previously demonstrated through over‐expression of the Wnt inhibitor dickkopf‐1 (DKK‐1) that Wnts contribute to the osteoblastic component of PCa osseous lesions in vivo. METHODS To test the clinical significance of DKK‐1 expression during PCa progression, tissue microarrays were stained for DKK‐1 protein by immunohistochemistry. RESULTS DKK‐1 expression index (EI) was found to increase in PIN and primary lesions compared to non‐neoplastic tissue (106 ± 10 vs. 19 ± 6, respectively, where the EI is the product of the percent expression and staining intensity). DKK‐1 expression was also found to be higher in all PCa metastatic lesions (56 ± 21 EI) compared to non‐neoplastic tissues but was significantly decreased versus primary PCa lesions (P < 0.008). The decline in DKK‐1 correlated with a shift of β‐catenin staining from the nucleus to the cytoplasm suggesting possible mechanism for the observed decrease in DKK‐1 levels during PCa progression. Within metastatic lesions, DKK‐1 expression was least abundant in PCa bone metastases relative to all soft tissue PCa metastatic lesions except lymph node metastases. High DKK‐1 expression within PCa metastases was further associated with shorter over‐all patient survival. CONCLUSIONS Taken together, these data demonstrate that elevated DKK‐1 expression is an early event in PCa and that as PCa progresses DKK‐1 expression declines, particularly in advanced bone metastases. The decline of DKK‐1 in bone metastases can unmask Wnts' osteoblastic activity. These data support a model in which DKK‐1 is a molecular switch that transitions the phenotype of PCa osseous lesions from osteolytic to osteoblastic. Prostate 68: 1396–1404, 2008.