ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors

Bone is the most common metastatic site for breast cancer. Estrogen-related-receptor alpha (ERR alpha) has been implicated in cancer cell invasiveness. Here, we established that ERR alpha 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 ERR alpha expression levels were associated with bone but not lung metastases. ERR alpha expression was also detected in circulating tumor cells from metastatic breast cancer patients. ERR alpha 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 ERR alpha expression level. In vivo, Rank was identified as a target for ERR alpha. 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 ERR alpha 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 ERR alpha/RANK in breast cancer patients and also revealed a positive correlation between ERR alpha and BRCA1(mut) carriers. Taken together, our results reveal a novel ERR alpha/RANK axis by which ERR alpha in primary breast cancer promotes early dissemination of cancer cells to bone. These findings suggest that ERR alpha may be a useful therapeutic target to prevent bone metastases.