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Elf5 inhibits the epithelial–mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2

Nature Cell Biology volume 14, pages 1212–1222 (2012)Cite this article

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Abstract

The epithelial–mesenchymal transition (EMT) is a complex process that occurs during organogenesis and in cancer metastasis. Despite recent progress, the molecular pathways connecting the physiological and pathological functions of EMT need to be better defined. Here we show that the transcription factor Elf5, a key regulator of mammary gland alveologenesis, controls EMT in both mammary gland development and metastasis. We uncovered this role for Elf5 through analyses of Elf5 conditional knockout animals, various in vitro and in vivo models of EMT and metastasis, an MMTV-neu transgenic model of mammary tumour progression and clinical breast cancer samples. Furthermore, we demonstrate that Elf5 suppresses EMT by directly repressing the transcription of Snail2, a master regulator of mammary stem cells and a known inducer of EMT. These findings establish Elf5 not only as a key cell lineage regulator during normal mammary gland development, but also as a suppressor of EMT and metastasis in breast cancer.

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Figure 1: Loss of Elf5 in the mouse mammary gland results in an EMT-like phenotype during pregnancy and lactation.
Figure 2: Loss of Elf5 leads to increased EMT gene expression programs.
Figure 3: Silencing ELF5 induces EMT in T47D cells and increases migratory potential.
Figure 4: Overexpression of Elf5 reverses mesenchymal characteristics of MDA-231 cells.
Figure 5: Elf5 binds to the SNAI2 promoter and represses its expression.
Figure 6: Expression pattern and prognostic values of ELF5 and SNAIL2 in breast tumours.
Figure 7: Elf5 inhibits lung metastasis in transplantable mouse models of metastasis.
Figure 8: Elf5 inhibits lung metastasis in the MMTV-Neu transgenic mouse model.

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Acknowledgements

We thank M. Korpal, B. I. Koh, H. Zheng and B. Ell for helpful discussions, M. Yuan and X. Hang for technical assistance, C. DeCoste for assistance with flow cytometry, J. Goodhouse for assistance with confocal microscopy and L. Cong and J. Friedman at the Tissue Analytic Service Core of Cancer Institute of New Jersey for assistance with clinical breast tumour sample immunohistochemistry analysis. This research was supported by grants from R01GM069417 to S.S., from the Breast Cancer Research Foundation to B.G.H. and Y.K. and from the Brewster Foundation, the Champalimaud Foundation, Komen for the Cure and the National Institutes of Health (R01CA134519 and R01CA141062) to Y.K. R.C. is a recipient of a DOD postdoctoral fellowship (W81XWH-11-1-0681) and M.A.B. is a recipient of an NRSA pre-doctoral fellowship from the National Institutes of Health.

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Author notes

  1. Qifeng Yang

    Present address: Present address: Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012, China,

  2. Julie Hwang and Mario Andres Blanco: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Molecular Biology, Princeton University, Princeton, New Jersey 08540, USA

    Rumela Chakrabarti, Julie Hwang, Mario Andres Blanco, Yong Wei, Martin Lukačišin & Yibin Kang

  2. Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, New York 14203, USA

    Rumela Chakrabarti, Rose-Anne Romano, Kirsten Smalley & Satrajit Sinha

  3. Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA

    Song Liu

  4. Department of Radiation Oncology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey 08901, USA

    Qifeng Yang & Bruce G. Haffty

  5. Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA

    Qifeng Yang, Bruce G. Haffty & Yibin Kang

  6. Osteoncology Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola, Italy

    Toni Ibrahim, Laura Mercatali & Dino Amadori

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Contributions

R.C., S.S. and Y.K. designed experiments. R.C., M.A.B., J.H., Y.W. and M.L. performed the experiments. R.R., K.S., S.L., Q.Y., T.I., L.M., D.A. and B.G.H. provided technical support. R.C., M.A.B. and Y.K. wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Julie Hwang, Mario Andres Blanco, Qifeng Yang, Satrajit Sinha or Yibin Kang.

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Chakrabarti, R., Hwang, J., Andres Blanco, M. et al. Elf5 inhibits the epithelial–mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2. Nat Cell Biol 14, 1212–1222 (2012). https://doi.org/10.1038/ncb2607

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