Research Papers:

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

Anais Fradet, Mathilde Bouchet, Carine Delliaux, Manon Gervais, Casina Kan, Claire Benetollo, Francesco Pantano, Geoffrey Vargas, Lamia Bouazza, Martine Croset, Yohann Bala, Xavier Leroy, Thomas J Rosol, Jennifer Rieusset, Akeila Bellahcène, Vincent Castronovo, Jane E Aubin, Philippe Clézardin, Martine Duterque-Coquillaud and Edith Bonnelye _

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Oncotarget. 2016; 7:77071-77086. https://doi.org/10.18632/oncotarget.12787

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Anais Fradet1,2,*, Mathilde Bouchet1,2,*, Carine Delliaux3,4, Manon Gervais1,2, Casina Kan1,2, Claire Benetollo2,5, Francesco Pantano6, Geoffrey Vargas1,2, Lamia Bouazza1,2, Martine Croset1,2, Yohann Bala1,2, Xavier Leroy7, Thomas J Rosol8, Jennifer Rieusset9, Akeila Bellahcène10, Vincent Castronovo10, Jane E Aubin11, Philippe Clézardin1,2, Martine Duterque-Coquillaud3,4, Edith Bonnelye1,2

1InsermUMR1033, F-69372 Lyon, France

2Université-Lyon1, F-69008 Lyon, France

3CNRS-UMR8161, F-59021 Lille, France

4Université-Lille, F-59000 Lille, France

5InsermU1028-CNRS-UMR5292, Lyon, France

6University-Campus-Bio-Medico, 00128 Rome, Italy

7Centre Hospitalier Lille, F-59037 Lille, France

8College of Veterinary Medicine, Columbus, OH 43210, USA

9InsermUMR-U1060, F-69921 Oullins, France

10University Liege, B-4000 Liege, Belgium

11University of Toronto, Toronto, ON M5S 1A8, Canada

*These authors contributed equally to this work

Correspondence to:

Edith Bonnelye, email: [email protected]

Keywords: ERRα, bone, prostate cancer, microenvironment

Received: July 04, 2016     Accepted: October 13, 2016     Published: October 20, 2016


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.

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