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miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1

Oncogene volume 30, pages 2463–2474 (2011)Cite this article

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Abstract

MicroRNAs (miRNAs) are involved in tumorigenecity by regulating specific oncogenes and tumor suppressor genes, and their roles in breast cancer stem cells (BCSCs) are becoming apparent. Distinct from the CD44+/CD24−/low sub-population, we have isolated a novel PROCR+/ESA+ BCSC sub-population. To explore miRNA-regulatory mechanisms in this sub-population, we performed miRNA expression profiling and found miR-495 as the most highly upegulated miRNA in PROCR+/ESA+ cells. Coincidently, high upregulation of miR-495 was also found in CD44+/CD24−/low BCSCs, reflecting its potential importance in maintaining common BCSC properties. Ectopic expression of miR-495 in breast cancer cells promoted their colony formation in vitro and tumorigenesis in mice. miR-495 directly suppressed E-cadherin expression to promote cell invasion and inhibited REDD1 expression to enhance cell proliferation in hypoxia through post-transcriptional mechanism. miR-495 expression was directly modulated by transcription factor E12/E47, which itself is highly expressed in BCSCs. These findings reveal a novel regulatory pathway centered on miR-495 that contributes to BCSC properties and hypoxia resistance.

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Acknowledgements

This work was supported by Academia Sinica Peak Project (grant number 2371, 4012); and an Academia Sinica Distinguished Postdocotral Fellowship and a Postdocotral Research Fellowship to WWHV. We thank Dr Paul E Verslues (Institute of Plant and Microbial Biology, Academia Sinica) for critical proofreading of the manuscript and Ms Meng-Han Wang for her kind assistance through this study.

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Authors and Affiliations

  1. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    W W Hwang-Verslues, P-H Chang, P-C Wei, C-Y Yang, C-K Huang, J-Y Shew, E Y-H P Lee & W-H Lee

  2. Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan

    W-H Kuo & K-J Chang

  3. Cheng Ching General Hospital, Taichung, Taiwan

    K-J Chang

  4. Department of Developmental and Cell Biology, University of California, Irvine, CA, USA

    E Y-H P Lee

  5. Department of Biological Chemistry, University of California, Irvine, CA, USA

    W-H Lee

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  1. W W Hwang-Verslues
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Correspondence to W-H Lee.

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WHL serves as a member of Board of Directors of GeneTex and has equity interest. This arrangement has been reviewed and approved by the UC Irvine Conflict of Interest committee. The remaining authors declare no conflict of interest.

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Hwang-Verslues, W., Chang, PH., Wei, PC. et al. miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1. Oncogene 30, 2463–2474 (2011). https://doi.org/10.1038/onc.2010.618

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