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RUNX1 prevents oestrogen-mediated AXIN1 suppression and β-catenin activation in ER-positive breast cancer

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  • Nyam-Osor Chimge

    (Keck School of Medicine of the University of Southern California
    Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California)

  • Gillian H. Little

    (Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California)

  • Sanjeev K. Baniwal

    (Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California)

  • Helty Adisetiyo

    (Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California)

  • Ying Xie

    (Brigham and Women's Hospital, Harvard Medical School)

  • Tian Zhang

    (Keck School of Medicine of the University of Southern California)

  • Andie O’Laughlin

    (Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California)

  • Zhi Y. Liu

    (Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California)

  • Peaches Ulrich

    (Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California)

  • Anthony Martin

    (Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California)

  • Paulette Mhawech-Fauceglia

    (Keck School of Medicine of the University of Southern California)

  • Matthew J. Ellis

    (Smith Breast Center, Baylor College of Medicine)

  • Debu Tripathy

    (The University of Texas MD Anderson Cancer Center)

  • Susan Groshen

    (Keck School of Medicine of the University of Southern California
    USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California)

  • Chengyu Liang

    (Keck School of Medicine of the University of Southern California)

  • Zhe Li

    (Brigham and Women's Hospital, Harvard Medical School)

  • Dustin E. Schones

    (Beckman Research Institute, City of Hope)

  • Baruch Frenkel

    (Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California
    USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California
    Keck School of Medicine of the University of Southern California
    Keck School of Medicine of the University of Southern California)

Abstract

Recent high-throughput studies revealed recurrent RUNX1 mutations in breast cancer, specifically in oestrogen receptor-positive (ER+) tumours. However, mechanisms underlying the implied RUNX1-mediated tumour suppression remain elusive. Here, by depleting mammary epithelial cells of RUNX1 in vivo and in vitro, we demonstrate combinatorial regulation of AXIN1 by RUNX1 and oestrogen. RUNX1 and ER occupy adjacent elements in AXIN1’s second intron, and RUNX1 antagonizes oestrogen-mediated AXIN1 suppression. Accordingly, RNA-seq and immunohistochemical analyses demonstrate an ER-dependent correlation between RUNX1 and AXIN1 in tumour biopsies. RUNX1 loss in ER+ mammary epithelial cells increases β-catenin, deregulates mitosis and stimulates cell proliferation and expression of stem cell markers. However, it does not stimulate LEF/TCF, c-Myc or CCND1, and it does not accelerate G1/S cell cycle phase transition. Finally, RUNX1 loss-mediated deregulation of β-catenin and mitosis is ameliorated by AXIN1 stabilization in vitro, highlighting AXIN1 as a potential target for the management of ER+ breast cancer.

Suggested Citation

  • Nyam-Osor Chimge & Gillian H. Little & Sanjeev K. Baniwal & Helty Adisetiyo & Ying Xie & Tian Zhang & Andie O’Laughlin & Zhi Y. Liu & Peaches Ulrich & Anthony Martin & Paulette Mhawech-Fauceglia & Mat, 2016. "RUNX1 prevents oestrogen-mediated AXIN1 suppression and β-catenin activation in ER-positive breast cancer," Nature Communications, Nature, vol. 7(1), pages 1-12, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10751
    DOI: 10.1038/ncomms10751
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