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

Nat Commun. 2016 Feb 26;7:10751. doi: 10.1038/ncomms10751.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axin Protein / genetics*
  • Axin Protein / metabolism
  • Blotting, Western
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Cyclin D1
  • Estrogens / metabolism*
  • Female
  • G1 Phase Cell Cycle Checkpoints
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunohistochemistry
  • MCF-7 Cells
  • Mice
  • Proto-Oncogene Proteins c-myc
  • Receptors, Estrogen / genetics*
  • Receptors, Estrogen / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • TCF Transcription Factors
  • beta Catenin / metabolism*

Substances

  • AXIN1 protein, human
  • Axin Protein
  • Axin1 protein, mouse
  • Core Binding Factor Alpha 2 Subunit
  • Estrogens
  • Proto-Oncogene Proteins c-myc
  • Receptors, Estrogen
  • TCF Transcription Factors
  • beta Catenin
  • Cyclin D1