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| Oncogene. 2018 Nov 26. doi: 10.1038/s41388-018-0579-3. pii: 10.1038/s41388-018-0579-3 |
| ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors. |
| Vargas G1, Bouchet M2, Bouazza L3, Reboul P4, Boyault C5, Gervais M6, Kan C7, Benetollo C8, Brevet M9, Croset M10, Mazel M11, Cayrefourcq L12, Geraci S13, Vacher S14, Pantano F15, Filipits M16, Driouch K17, Bieche I18, Gnant M19, Jacot W20, Aubin JE21, Duterque-Coquillaud M22, Alix-Panabières C23, Clézardin P24, Bonnelye E25 |
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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 BRCA1 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. |
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Publikations ID: 30478447 Quelle: öffnen |
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