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

Anaïs Fradet (1) , Mathilde Bouchet (1) , Carine Delliaux (2) , Manon Gervais (1) , Casina E Kan (1) , Claire Benetollo (3) , Francesco Pantano (4) , Geoffrey Vargas (1) , Lamia Bouazza (1) , Martine E Croset (1) , Yohann Bala (1) , Xavier Leroy (5) , Thomas J Rosol (6) , Jennifer Rieusset (7) , Akeila Bellahcène (8) , Vincent Castronovo (8) , Jane Aubin (9) , Philippe Clezardin (1) , Martine Duterque-Coquillaud (2) , Edith E Bonnelye (1)

1 LYOS - Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases
2 M3T - Mécanismes de la Tumorigénèse et Thérapies Ciblées - UMR 8161
3 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
4 UCBM - Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome
5 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
6 College of Veterinary Medicine [Colombus]
7 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
8 Université de Liège
9 University of Toronto

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.

Mots clés: prostate cancer; ERRα; microenvironment; bone

Domaines: Cancer; Biochimie, Biologie Moléculaire; Urologie et Néphrologie

Anaïs Fradet, Mathilde Bouchet, Carine Delliaux, Manon Gervais, Casina E Kan, et al.. Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone. Oncotarget, 2016, 7 (47), pp.77071-77086. ⟨10.18632/oncotarget.12787⟩. ⟨hal-02353264⟩