RUNX1 prevents oestrogen-mediated AXIN1 suppression and β-catenin activation in ER-positive breast cancer
Copyright policy )RUNX1 prevents oestrogen-mediated AXIN1 suppression and β-catenin activation in ER-positive breast cancer
AbstractRecent high-throughput studies revealed recurrentRUNX1mutations 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 RUNX1in vivoandin vitro,we demonstrate combinatorial regulation ofAXIN1by RUNX1 and oestrogen. RUNX1 and ER occupy adjacent elements inAXIN1’s second intron, and RUNX1 antagonizes oestrogen-mediatedAXIN1suppression. 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-MycorCCND1,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 stabilizationin vitro, highlighting AXIN1 as a potential target for the management of ER+breast cancer.
- Harvard University United States
- University of California System United States
- Brigham and Women's Faulkner Hospital United States
- Baylor College of Medicine United States
- The University of Texas MD Anderson Cancer Center United States
570, Science, Blotting, Western, 610, Breast Neoplasms, Article, Proto-Oncogene Proteins c-myc, Mice, Axin Protein, Animals, Humans, Cyclin D1, beta Catenin, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Q, Estrogens, G1 Phase Cell Cycle Checkpoints, Immunohistochemistry, Gene Expression Regulation, Neoplastic, Receptors, Estrogen, Core Binding Factor Alpha 2 Subunit, MCF-7 Cells, Female, TCF Transcription Factors
570, Science, Blotting, Western, 610, Breast Neoplasms, Article, Proto-Oncogene Proteins c-myc, Mice, Axin Protein, Animals, Humans, Cyclin D1, beta Catenin, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Q, Estrogens, G1 Phase Cell Cycle Checkpoints, Immunohistochemistry, Gene Expression Regulation, Neoplastic, Receptors, Estrogen, Core Binding Factor Alpha 2 Subunit, MCF-7 Cells, Female, TCF Transcription Factors
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