| Title: |
ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors |
| Authors: |
Vargas, G; Bouchet, M; Bouazza, L; Reboul, P; Boyault, C; Gervais, M; Kan, C; Benetollo, C; Brevet, M; Croset, M; Mazel, M; Cayrefourcq, L; Geraci, S; Vacher, S; Pantano, F; Filipits, M; Driouch, K; Bieche, I; Gnant, M.; Jacot, W; Aubin, J.E.; Duterque-Coquillaud, M; Alix-Panabières, C; Clézardin, P; Bonnelye, E |
| Contributors: |
Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases LYOS; Institut de Génomique Fonctionnelle de Lyon IGFL; Ingénierie Moléculaire et Physiopathologie Articulaire IMoPA; Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) IAB; The University of Sydney; Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center CRNL; Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 AIDMP; Institut Curie Paris; Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome UCBM; Medizinische Universität Wien = Medical University of Vienna; Institut de Recherche en Cancérologie de Montpellier IRCM - U1194 Inserm - UM; Institut de biologie de Lille - IBL IBLI; Mécanismes de tumorigenèse et thérapies ciblées |
| Publisher Information: |
Nature Publishing Group |
| Publication Year: |
2019 |
| Collection: |
LillOA (Lille Open Archive - Université de Lille) |
| Subject Terms: |
Animals; Bone Neoplasms/genetics; Breast Neoplasms/metabolism; Breast Neoplasms/pathology; Humans; Female; Gene Expression Regulation; Neoplastic; Mammary Neoplasms; Animal/genetics; Animal/metabolism; Animal/pathology; Mice; Inbred BALB C; Receptor Activator of Nuclear Factor-kappa B/biosynthesis; Neoplasm Proteins/genetics; Neoplasm Proteins/metabolism; Receptor Activator of Nuclear Factor-kappa B/genetics; Bone Neoplasms/metabolism; Receptors; Estrogen/genetics; Estrogen/metabolism; Bone Neoplasms/pathology; Breast Neoplasms/genetics; Bone Neoplasms/secondary |
| Description: |
Bone is the most common metastatic site for breast cancer. Estrogen-related-receptor alpha (ERRα) has been implicated in cancer cell invasiveness. Here, we established that ERRα promotes spontaneous metastatic dissemination of breast cancer cells from primary mammary tumors to the skeleton. We carried out cohort studies, pharmacological inhibition, gain-of-function analyses in vivo and cellular and molecular studies in vitro to identify new biomarkers in breast cancer metastases. Meta-analysis of human primary breast tumors revealed that high ERRα expression levels were associated with bone but not lung metastases. ERRα expression was also detected in circulating tumor cells from metastatic breast cancer patients. ERRα overexpression in murine 4T1 breast cancer cells promoted spontaneous bone micro-metastases formation when tumor cells were inoculated orthotopically, whereas lung metastases occurred irrespective of ERRα expression level. In vivo, Rank was identified as a target for ERRα. That was confirmed in vitro in Rankl stimulated tumor cell invasion, in mTOR/pS6K phosphorylation, by transactivation assay, ChIP and bioinformatics analyses. Moreover, pharmacological inhibition of ERRα reduced primary tumor growth, bone micro-metastases formation and Rank expression in vitro and in vivo. Transcriptomic studies and meta-analysis confirmed a positive association between metastases and ERRα/RANK in breast cancer patients and also revealed a positive correlation between ERRα and BRCA1 mut carriers. Taken together, our results reveal a novel ERRα/RANK axis by which ERRα in primary breast cancer promotes early dissemination of cancer cells to bone. These findings suggest that ERRα may be a useful therapeutic target to prevent bone metastases. |
| Document Type: |
conference object |
| File Description: |
application/octet-stream |
| Language: |
English |
| Relation: |
http://hdl.handle.net/20.500.12210/55264 |
| Availability: |
https://hdl.handle.net/20.500.12210/55264 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.1A699B73 |
| Database: |
BASE |