Men with
castration-resistant
prostate cancer (PCa) frequently develop
metastasis in bone. The reason for this association is unclear. We have previously shown that
cadherin-11 (also known as
OB-cadherin), a homophilic
cell adhesion molecule that mediates osteoblast adhesion, plays a role in the
metastasis of PCa to bone. Here, we report that
androgen-deprivation
therapy up-regulates
cadherin-11 expression in PCa. In human PCa specimens, immunohistochemical staining showed that 22/26 (85%) primary PCa tumours from men with
castration-resistant PCa expressed
cadherin-11. In contrast, only 7/50 (14%)
androgen-dependent PCa tumours expressed
cadherin-11. In the MDA-PCa-2b xenograft animal model,
cadherin-11 was expressed in the recurrent tumours following
castration. In the PCa cell lines, there is an inverse correlation between expression of
cadherin-11 and
androgen receptor (AR), and
cadherin-11 is expressed in very low levels or not expressed in AR-positive cell lines, including LNCaP, C4-2B4 and VCaP cells. We showed that AR likely regulates
cadherin-11 expression in PCa through an indirect mechanism. Although re-expression of AR in the AR-negative PC3 cells led to the inhibition of
cadherin-11 expression, depletion of
androgen from the culture medium or down-regulation of AR by RNA interference in the C4-2B4 cells or VCaP cells only produced a modest increase of
cadherin-11 expression. Promoter analysis indicated that
cadherin-11 promoter does not contain a typical AR-binding
element, and AR elicits a modest inhibition of
cadherin-11 promoter activity, suggesting that AR does not regulate
cadherin-11 expression directly. Together, these results suggest that
androgen deprivation up-regulates
cadherin-11 expression in
prostate cancer, and this may contribute to the
metastasis of PCa to bone. Our study suggests that therapeutic strategies that block
cadherin-11 expression or function may be considered when applying
androgen-ablation
therapy.