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MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11

Nature Communications volume 4, Article number: 1393 (2013) | Download Citation

Abstract

Chemotherapy resistance frequently drives tumour progression. However, the underlying molecular mechanisms are poorly characterized. Epithelial-to-mesenchymal transition has been shown to correlate with therapy resistance, but the functional link and signalling pathways remain to be elucidated. Here we report that microRNA-30c, a human breast tumour prognostic marker, has a pivotal role in chemoresistance by a direct targeting of the actin-binding protein twinfilin 1, which promotes epithelial-to-mesenchymal transition. An interleukin-6 family member, interleukin-11 is identified as a secondary target of twinfilin 1 in the microRNA-30c signalling pathway. Expression of microRNA-30c inversely correlates with interleukin-11 expression in primary breast tumours and low interleukin-11 correlates with relapse-free survival in breast cancer patients. Our study demonstrates that microRNA-30c is transcriptionally regulated by GATA3 in breast tumours. Identification of a novel microRNA-mediated pathway that regulates chemoresistance in breast cancer will facilitate the development of novel therapeutic strategies.

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Acknowledgements

We thank Drs Marcus Peter, Suzanne Conzen and Yves Lussier for suggestions and comments on the project and manuscript. We appreciate the experimental support of several core facilities, including animal facility, optical imaging core facility, flow cytometry facility, integrated microscopy core facility, DNA sequencing facility, functional genomics facility and IHC core facility at the University of Chicago. We specifically acknowledge Ryan Duggan, James Cao, David Leclerc, Marianne Greene, Terri Li, Xin Jiang, Shirley Bond, Jaejung Kim, Hui Zheng, Andrew Gusev, Dalong Qian, Yohei Shimono and Ravand Samaeekia for technical help and support. This study was supported in part by The University of Chicago Women’s Board (J.B.), National Institutes of Health (NIH) T90 Regenerative Medicine Training Program DK070103-05, Department of Defense Breast Cancer Research Program W81XWH-09-1-0331, Paul Calabresi K12 Award 1K12CA139160-02, NCI K99 CA160638-01, Chicago Fellows Program at the University of Chicago, and the University of Chicago Clinical and Translational Science Award (UL1 RR024999; H.L.), The University of Chicago Cancer Research Center Pilot Fund, BSD Imaging Research Institute Pilot Research Projects Using Animal Imaging, UCMC/Northshore Collaborative Funds, a Segal Grant and the Virginia and D. K. Ludwig Fund (G.L.G. and H.L.), funds from the Sociedad Española de Oncología Médica (SEOM; A.P.), the Breast SPORE at University of North Carolina 5-P50-CA58223-17 (A.P. and C.M.P.), 1R21CA159066 (D.H.), NIH R21 CA139278 and Pharmacogenetics of Anticancer Agents Research Group UO1GM61393 (M.E.D), NIH Grants U54 CA 126524 and P01 CA139490 (M.F.C.), the Breast Cancer Research Foundation (M.F.C., O.I.O. and C.M.P.), the Breast SPORE P50CA125183-05, the Doris Duke Charitable Foundation (O.I.O and C.N.) and the University of Chicago Cancer Centre Support Grant CA 014599.

Author information

Author notes

    • Aleix Prat

    Present address: Translational Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain

Affiliations

  1. The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA

    • Jessica Bockhorn
    • , Rachel Dalton
    • , Simo Huang
    • , Kathy Yee
    • , Ya-Fang Chang
    • , Kaitlin E. Swanson
    • , Tyler Qiu
    • , Geoffrey L. Greene
    •  & Huiping Liu
  2. Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA

    • Jessica Bockhorn
  3. Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL 60637, USA

    • Chika Nwachukwu
    •  & Olufunmilayo I. Olopade
  4. Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA

    • Chika Nwachukwu
    • , Yujia Wen
    • , M. Eileen Dolan
    •  & Olufunmilayo I. Olopade
  5. Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    • Aleix Prat
    •  & Charles M. Perou
  6. Department of Health Studies, University of Chicago, Chicago, Illinois 60637, USA

    • Dezheng Huo
    •  & Seo Young Park
  7. Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, Illinois 60637, USA

    • Yujia Wen
    •  & M. Eileen Dolan
  8. Department of Genetics, Yale Stem Cell Center and Yale Cancer Center, Yale University, New Haven, Connecticut 06520, USA

    • Jun Lu
  9. The Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California 94305, USA

    • Michael F. Clarke
    •  & Huiping Liu

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Contributions

J.B., R.D., C.N. and S.H. contributed equally to this manuscript. J.B., R.D., C.N., S.H., A.P., K.Y., Y-F.C., Y.W., K.E.S., T.Q. and H.L. designed and performed experiments, and analysed data. J.L. provided the miRNA entry clones and the gateway vector backbone. S.Y.P. and D.H. performed biostatistical analyses for animal work and association studies. M.E.D., C.M.P., O.I.O., M.F.C. and G.L.G. designed the project. J.B. and H.L. wrote the manuscript. G.L.G., M.F.C., O.I.O., A.P., D.H., S.H., C.N. and M.E.D. contributed to the editing of the manuscript. G.L.G., M.F.C., O.I.O. and H.L. are equally contributing senior authors on this manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Huiping Liu.

Supplementary information

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    Supplementary Information

    Supplementary Figures S1-S8, Supplementary Tables S1-S9 and Supplementary References

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    Supplementary Data 1

    SAM analyses of miR-30c regulated genes

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DOI

https://doi.org/10.1038/ncomms2393

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