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.

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Acknowledgements

The authors thank Anne Flourens, Cyprien Tilmant, Tina Louadj, and both CeCIL and ALECS platforms (Faculté de Médecine Laennec, Lyon) for their assistance.

Funding

This work was supported by the National Center for Scientific Research (CNRS) to EB, the National Institute of Health and Medical Research (INSERM), the University of Lyon1, La Ligue Nationale (Drôme), Inserm-Transfert (EB). GV was supported by the Labex DEVweCAN, MG, MB by the French National Cancer Institute (INCa), CK by the Marie-Curie-Individual-Fellowship (655777-miROMeS). CAP, LC, and MM by CANCER-ID (FP7/2007-2013) and EFPIA.

Author information

Affiliations

  1. INSERM-UMR1033, Lyon, France

    • G. Vargas
    • , M. Bouchet
    • , L. Bouazza
    • , M. Gervais
    • , C. Kan
    • , M. Brevet
    • , M. Croset
    • , S. Geraci
    • , P. Clézardin
    •  & E. Bonnelye
  2. University of Lyon1, Lyon, France

    • G. Vargas
    • , M. Bouchet
    • , L. Bouazza
    • , M. Gervais
    • , C. Kan
    • , C. Benetollo
    • , M. Croset
    • , S. Geraci
    • , P. Clézardin
    •  & E. Bonnelye
  3. IGFL, Lyon, France

    • M. Bouchet
  4. UMR7365-CNRS-Université de Lorraine, Nancy, France

    • P. Reboul
  5. Institute for Advanced Biosciences, Grenoble, France

    • C. Boyault
  6. Center for Cancer Research, University of Sydney, Sydney, Australia

    • C. Kan
  7. INSERM-U1028-CNRS-UMR5292, Lyon, France

    • C. Benetollo
  8. Centre de Biologie et de Pathologie Est, Bron, France

    • M. Brevet
  9. EA2415-Institut Universitaire de Recherche Clinique, Montpellier, France

    • M. Mazel
    • , L. Cayrefourcq
    •  & C. Alix-Panabières
  10. Department of Genetics, Institut-Curie, Paris, France

    • S. Vacher
    • , K. Driouch
    •  & I. Bieche
  11. University-Campus-Bio-Medico, Rome, 00128, Italy

    • F. Pantano
  12. Department of Surgery and Comprehensive Cancer Center, Medical-University of Vienna, Vienna, Austria

    • M. Filipits
    •  & M. Gnant
  13. Montpellier Cancer Institute, Montpellier, France

    • W. Jacot
  14. University of Toronto, Toronto, Canada

    • J. E. Aubin
  15. UMR8161/CNRS-Institut de Biologie de Lille, Lille, France

    • M. Duterque-Coquillaud

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Correspondence to E. Bonnelye.

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https://doi.org/10.1038/s41388-018-0579-3