ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors.
Oncogene
; 38(7): 950-964, 2019 02.
Article
de En
| MEDLINE
| ID: mdl-30478447
ABSTRACT
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 BRCA1mut 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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Tumeurs osseuses
/
Tumeurs du sein
/
Récepteurs des oestrogènes
/
Régulation de l'expression des gènes tumoraux
/
Tumeurs mammaires de l'animal
/
Récepteur activateur du facteur nucléaire Kappa B
/
Protéines tumorales
Type d'étude:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limites:
Animals
/
Female
/
Humans
Langue:
En
Journal:
Oncogene
Sujet du journal:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Année:
2019
Type de document:
Article
Pays d'affiliation:
France