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miR-155 promotes macroscopic tumor formation yet inhibits tumor dissemination from mammary fat pads to the lung by preventing EMT

Oncogene volume 30, pages 3440–3453 (2011)Cite this article

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Abstract

A micro-RNA, miR-155, is overexpressed in many types of cancer cells, including breast cancer, and its role(s) in tumor metastasis has been studied on a very limited basis. Tumor metastasis is a multi-step process with the last step in the process being formation of macroscopic tumor in organs distant from the primary tumor site. This step is the least studied. Here, we report that stable expression of miR-155 in 4T1 breast tumor cells reduces significantly the aggressiveness of tumor cell dissemination as a result of preventing epithelial-to-mesenchymal transition (EMT) of tumor cells in vivo. Further, miR-155 directly suppresses the expression of the transcription factor TCF4, which is an important regulator of EMT. However, when tumor cells are injected directly into the bloodstream, miR-155 remarkably promotes macroscopic tumor formation in the lung. Analysis of gene expression profiling identified a group of genes that are associated with promoting macroscopic tumor formation in the lung. Importantly, most of these genes are overexpressed in epithelial cells. Our findings provide new insight into how miR-155 modulates the development of tumor metastasis. This study suggests that the location of tumor cells overexpressing miR-155 is a critical factor: in mammary fat pads miR-155 prevents tumor dissemination; whereas in the lung miR-155 apparently maintains the epithelial phenotype of tumor cells that is critical for macroscopic tumor formation.

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Acknowledgements

We thank Dr David L Turner for providing plasmid UAS-luc-miR-155as, Dr David P Bartel for MDH1-PGK-GFP-miR-223 plasmid and Dr Jeffrey Schlom for the AT-3 breast tumor cell line. This work was supported by grants from the National Institutes of Health (NIH) (RO1CA137037, R01AT004294, RO1CA107181 and RO1CA116092), the Louisville Veterans Administration Medical Center (VAMC) Merit Review Grants (H-G Z) and a grant from the Susan G Komen Breast Cancer Foundation. We thank Dr Jerald Ainsworth for editorial assistance.

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Authors and Affiliations

  1. Department of Microbiology & Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA

    X Xiang, X Zhuang, S Ju, H Jiang, J Mu, L Zhang, D Miller & H-G Zhang

  2. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    S Zhang & W Grizzle

  3. Louisville Veterans Administration Medical Center, Louisville, KY, USA

    H-G Zhang

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  1. X Xiang
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Correspondence to X Xiang.

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Xiang, X., Zhuang, X., Ju, S. et al. miR-155 promotes macroscopic tumor formation yet inhibits tumor dissemination from mammary fat pads to the lung by preventing EMT. Oncogene 30, 3440–3453 (2011). https://doi.org/10.1038/onc.2011.54

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