Eighty percent of patients dying from prostate carcinoma (PCa) have developed bone metastases that are incurable. Because we found the orphan nuclear receptor oestrogen receptor-related receptor alpha (ERRa) expressed in bone metastases from PCa patients, we modulated its expression in PC3 cells. We showed that PC3 cells over-expressing WT ERRa (PC3-ERRa) stimulate rapidly osteolytic bone lesions in SCID mice (n=10) (1.20±0.34* for osteolysis (mm2) and 18.5±5.4** for skeletal tumor burden (TB/STV) (%)) compared with that observed with PC3-CT cells (0.49±0.22 (osteolysis) and 2±0.73 (TB/STV)) (Ethical approval DR2014-32). Surprisingly bone destruction was combined with new bone formation, as 70% of the metastatic limbs bearing PC3-ERRa cells had mixed lesions compared with CT-PC3 that are only osteolytic. Osteoclasts were directly affected in vivo and in vitro which was associated with the stimulation of pro-osteoclastic factors mRNA of Cox2, Runx2, and cathepsin K by PC3-ERRa. Moreover, a statistical stimulation of bone formation in calvaria culture was observed when cells were co-cultured with PC3-ERRa. This was combined with the up-regulation of ET1, Wnt3a and Wnt5a that may explain the occurrence of bone formation in vivo. Interestingly, tumoural microenvironment was also affected by PC3-ERRa cells, as mouse periostin (POSTN), was over-expressed by the cancer-associated-fibroblasts in vivo. Moreover, we found that PC3-ERRa inhibits spheres formation, which was associated with a decrease of Nanog and Oct4 expression in vivo. Finally, we showed that elevated expression of ERRa mRNA in PCa (cohort of 60 patients) (Ethical approval CSTMT-042) is associated with high level of ET1, Cox2, POSTN, and Wnt5a. In conclusion, our data provided for the first time evidence that ERRa can promote both osteolysis and osteosclerosis in animal models of PCa bone metastases. They also suggest its implication in the stromal niche via the POSTN/Wnt signalling and in the inhibition of the self-renewal capacity and pluripotency of tumour cells.
Disclosure: The authors declared no competing interests. This work was funded by the French National Cancer Institute (INCa) and Association for Prostate Tumor Research (ARTP).