[en] Bone metastases are one of the main complications of prostate cancer and they are incurable. We investigated whether and how estrogen receptor-related receptor alpha (ERRalpha) is involved in bone tumor progression associated with advanced prostate cancer. By meta-analysis, we first found that ERRalpha expression is correlated with castration-resistant prostate cancer (CRPC), the hallmark of progressive disease. We then analyzed tumor cell progression and the associated signaling pathways in gain-of-function/loss-of-function CRPC models in vivo and in vitro. Increased levels of ERRalpha in tumor cells led to rapid tumor progression, with both bone destruction and formation, and direct impacts on osteoclasts and osteoblasts. VEGF-A, WNT5A and TGFbeta1 were upregulated by ERRalpha in tumor cells and all of these factors also significantly and positively correlated withERRalpha expression in CRPC patient specimens. Finally, high levels of ERRalpha in tumor cells stimulated the pro-metastatic factor periostin expression in the stroma, suggesting that ERRalpha regulates the tumor stromal cell microenvironment to enhance tumor progression. Taken together, our data demonstrate that ERRalpha is a regulator of CRPC cell progression in bone. Therefore, inhibiting ERRalpha may constitute a new therapeutic strategy for prostate cancer skeletal-related events.
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