Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone

// Anais Fradet 1, 2, * , Mathilde Bouchet 1, 2, * , Carine Delliaux 3, 4 , Manon Gervais 1, 2 , Casina Kan 1, 2 , Claire Benetollo 2, 5 , Francesco Pantano 6 , Geoffrey Vargas 1, 2 , Lamia Bouazza 1, 2 , Martine Croset 1, 2 , Yohann Bala 1, 2 , Xavier Leroy 7 , Thomas J Rosol 8 , Jennifer Rieusset 9 , Akeila Bellahcene 10 , Vincent Castronovo 10 , Jane E Aubin 11 , Philippe Clezardin 1, 2 , Martine Duterque-Coquillaud 3, 4 , Edith Bonnelye 1, 2 1 InsermUMR1033, F-69372 Lyon, France 2 Universite-Lyon1, F-69008 Lyon, France 3 CNRS-UMR8161, F-59021 Lille, France 4 Universite-Lille, F-59000 Lille, France 5 InsermU1028-CNRS-UMR5292, Lyon, France 6 University-Campus-Bio-Medico, 00128 Rome, Italy 7 Centre Hospitalier Lille, F-59037 Lille, France 8 College of Veterinary Medicine, Columbus, OH 43210, USA 9 InsermUMR-U1060, F-69921 Oullins, France 10 University Liege, B-4000 Liege, Belgium 11 University of Toronto, Toronto, ON M5S 1A8, Canada * These authors contributed equally to this work Correspondence to: Edith Bonnelye, email: edith.bonnelye@inserm.fr Keywords: ERRα, bone, prostate cancer, microenvironment Received: July 04, 2016      Accepted: October 13, 2016      Published: October 20, 2016 ABSTRACT 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 ( ERRα ) is involved in bone tumor progression associated with advanced prostate cancer. By meta-analysis, we first found that ERRα 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 ERRα 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 TGFβ1 were upregulated by ERRα in tumor cells and all of these factors also significantly and positively correlated with ERRα expression in CRPC patient specimens. Finally, high levels of ERRα in tumor cells stimulated the pro-metastatic factor periostin expression in the stroma, suggesting that ERRα regulates the tumor stromal cell microenvironment to enhance tumor progression. Taken together, our data demonstrate that ERRα is a regulator of CRPC cell progression in bone. Therefore, inhibiting ERRα may constitute a new therapeutic strategy for prostate cancer skeletal-related events.