title: RUNX1 prevents oestrogen-mediated AXIN1 suppression and β-catenin activation in ER-positive breast cancer.
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.
authors.affiliation: Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.|Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Nyam-Osor
authors.initials: NO
authors.lastname: Chimge
authors.affiliation: Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Gillian H
authors.initials: GH
authors.lastname: Little
authors.affiliation: Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Baniwal
authors.affiliation: Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Helty
authors.initials: H
authors.lastname: Adisetiyo
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Andie
authors.initials: A
authors.lastname: O'Laughlin
authors.affiliation: Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Zhi Y
authors.initials: ZY
authors.lastname: Liu
authors.affiliation: Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Peaches
authors.initials: P
authors.lastname: Ulrich
authors.affiliation: Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Martin
authors.affiliation: Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Paulette
authors.initials: P
authors.lastname: Mhawech-Fauceglia
authors.affiliation: Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Debu
authors.initials: D
authors.lastname: Tripathy
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.|USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liang
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, California 91010, USA.
authors.forename: Dustin E
authors.initials: DE
authors.lastname: Schones
authors.affiliation: Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.|USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.|Department of Orthopedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.|Department of Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Baruch
authors.initials: B
authors.lastname: Frenkel
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D019938:Cyclin D1; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051820:TCF Transcription Factors; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C555451:AXIN1 protein, human; D060466:Axin Protein; C555452:Axin1 protein, mouse; D050676:Core Binding Factor Alpha 2 Subunit; D004967:Estrogens; D016271:Proto-Oncogene Proteins c-myc; D011960:Receptors, Estrogen; D051820:TCF Transcription Factors; D051176:beta Catenin; D019938:Cyclin D1