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

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, Matthew J. Ellis, Debu Tripathy, Susan Groshen, Chengyu Liang, Zhe Li, Dustin E. Schones and Baruch Frenkel
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Nyam-Osor Chimge: 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
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

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10751

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