ERR[alpha] 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.sup.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.