title: Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone.
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 withERRα 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.
authors: InsermUMR1033, F-69372 Lyon, France.|Université-Lyon1, F-69008 Lyon, France.
authors: Anais
authors: A
authors: Fradet
authors: InsermUMR1033, F-69372 Lyon, France.|Université-Lyon1, F-69008 Lyon, France.
authors: Mathilde
authors: M
authors: Bouchet
authors: CNRS-UMR8161, F-59021 Lille, France.|Université-Lille, F-59000 Lille, France.
authors: Carine
authors: C
authors: Delliaux
authors: InsermUMR1033, F-69372 Lyon, France.|Université-Lyon1, F-69008 Lyon, France.
authors: Manon
authors: M
authors: Gervais
authors: InsermUMR1033, F-69372 Lyon, France.|Université-Lyon1, F-69008 Lyon, France.
authors: Casina
authors: C
authors: Kan
authors: Université-Lyon1, F-69008 Lyon, France.|InsermU1028-CNRS-UMR5292, Lyon, France.
authors: Claire
authors: C
authors: Benetollo
authors: University-Campus-Bio-Medico, 00128 Rome, Italy.
authors: Francesco
authors: F
authors: Pantano
authors: InsermUMR1033, F-69372 Lyon, France.|Université-Lyon1, F-69008 Lyon, France.
authors: Geoffrey
authors: G
authors: Vargas
authors: InsermUMR1033, F-69372 Lyon, France.|Université-Lyon1, F-69008 Lyon, France.
authors: Lamia
authors: L
authors: Bouazza
authors: InsermUMR1033, F-69372 Lyon, France.|Université-Lyon1, F-69008 Lyon, France.
authors: Martine
authors: M
authors: Croset
authors: InsermUMR1033, F-69372 Lyon, France.|Université-Lyon1, F-69008 Lyon, France.
authors: Yohann
authors: Y
authors: Bala
authors: Centre Hospitalier Lille, F-59037 Lille, France.
authors: Xavier
authors: X
authors: Leroy
authors: College of Veterinary Medicine, Columbus, OH 43210, USA.
authors: Thomas J
authors: TJ
authors: Rosol
authors: InsermUMR-U1060, F-69921 Oullins, France.
authors: Jennifer
authors: J
authors: Rieusset
authors: University Liege, B-4000 Liege, Belgium.
authors: Akeila
authors: A
authors: Bellahcène
authors: University Liege, B-4000 Liege, Belgium.
authors: Vincent
authors: V
authors: Castronovo
authors: Department of Molecular Genetics, University-Toronto, Toronto, ON M5S 1A8, Canada.
authors: Jane E
authors: JE
authors: Aubin
authors: InsermUMR1033, F-69372 Lyon, France.|Université-Lyon1, F-69008 Lyon, France.
authors: Philippe
authors: P
authors: Clézardin
authors: CNRS-UMR8161, F-59021 Lille, France.|Université-Lille, F-59000 Lille, France.
authors: Martine
authors: M
authors: Duterque-Coquillaud
authors: InsermUMR1033, F-69372 Lyon, France.|Université-Lyon1, F-69008 Lyon, France.
authors: Edith
authors: E
authors: Bonnelye
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000071818:Wnt-5a Protein / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D015815:Cell Adhesion Molecules; D011960:Receptors, Estrogen; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D000071818:Wnt-5a Protein; D000097983:ERRalpha Estrogen-Related Receptor; C512835:POSTN protein, human; C508960:TGFB1 protein, human; C467484:VEGFA protein, human; C085389:WNT5A protein, human
keywords: ERRα; bone; microenvironment; prostate cancer