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MiR-200 can repress breast cancer metastasis through ZEB1-independent but moesin-dependent pathways

Oncogene volume 33, pages 4077–4088 (2014)Cite this article

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Abstract

The microRNA-200 (miR-200) family has a critical role in regulating epithelial–mesenchymal transition and cancer cell invasion through inhibition of the E-cadherin transcriptional repressors ZEB1 and ZEB2. Recent studies have indicated that the miR-200 family may exert their effects at distinct stages in the metastatic process, with an overall effect of enhancing metastasis in a syngeneic mouse breast cancer model. We find in a xenograft orthotopic model of breast cancer metastasis that ectopic expression of members of the miR-200b/200c/429, but not the miR-141/200a, functional groups limits tumour cell invasion and metastasis. Despite modulation of the ZEB1-E-cadherin axis, restoration of ZEB1 in miR-200b-expressing cells was not able to alter metastatic potential suggesting that other targets contribute to this process. Instead, we found that miR-200b repressed several actin-associated genes, with the knockdown of the ezrin-radixin-moesin family member moesin alone phenocopying the repression of cell invasion by miR-200b. Moesin was verified to be directly targeted by miR-200b, and restoration of moesin in miR-200b-expressing cells was sufficient to alleviate metastatic repression. In breast cancer cell lines and patient samples, the expression of moesin significantly inversely correlated with miR-200 expression, and high levels of moesin were associated with poor relapse-free survival. These findings highlight the context-dependent effects of miR-200 in breast cancer metastasis and demonstrate the existence of a moesin-dependent pathway, distinct from the ZEB1-E-cadherin axis, through which miR-200 can regulate tumour cell plasticity and metastasis.

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Acknowledgements

We thank Professor Joan Massague for providing the MDA-MB-231 LM2 cell line and Dr Ross Dickins for providing the pLMP-puro-GFP construct. We thank Dr Agatha Labrinidis and Ms Yuka Harata-Lee for assistance with bioluminescence imaging and inoculation of tumour cells, respectively, Dr Peter Diamond for help with bone histological analysis and Professors Andreas Evdokiou and Shaun McColl for insightful discussions. This work was supported by fellowships from the National Breast Cancer Foundation of Australia (PAG, CPB and RLA, nos ECF-09-08 and PF-09-03) and grants from the National Health and Medical Research Council of Australia (PAG, YK-G, GJG, RLA and CNJ, nos 566871 and APP1020280), Cancer Council South Australia (GJG, PAG and YK-G) and Prostate Cancer Foundation of Australia (LAS, no. YI 0810).

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  1. P A Gregory and Y Khew-Goodall: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia

    X Li, S Roslan, J A Wright, C P Bracken, M Anderson, A G Bert, G J Goodall, P A Gregory & Y Khew-Goodall

  2. Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia

    C N Johnstone & R L Anderson

  3. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia

    C N Johnstone & R L Anderson

  4. Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia

    C N Johnstone & R L Anderson

  5. Department of Pharmacology, The University of Melbourne, Parkville, Victoria, Australia

    C N Johnstone

  6. Discipline of Medicine, The University of Adelaide, Adelaide, South Australia, Australia

    J A Wright, C P Bracken, G J Goodall & P A Gregory

  7. Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, University of Adelaide, Hanson Institute, Adelaide, South Australia, Australia

    L A Selth

  8. School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia, Australia

    G J Goodall & Y Khew-Goodall

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Correspondence to P A Gregory or Y Khew-Goodall.

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Li, X., Roslan, S., Johnstone, C. et al. MiR-200 can repress breast cancer metastasis through ZEB1-independent but moesin-dependent pathways. Oncogene 33, 4077–4088 (2014). https://doi.org/10.1038/onc.2013.370

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