title: DMXL2 drives epithelial to mesenchymal transition in hormonal therapy resistant breast cancer through Notch hyper-activation.
abstract: The acquisition of endocrine therapy resistance in estrogen receptor α (ERα) breast cancer patients represents a major clinical problem. Notch signalling has been extensively linked to breast cancer especially in patients who fail to respond to endocrine therapy. Following activation, Notch intracellular domain is released and enters the nucleus where activates transcription of target genes. The numerous steps that cascade after activation of the receptor complicate using Notch as biomarker. Hence, this warrants the development of reliable indicators of Notch activity. DMXL2 is a novel regulator of Notch signalling not yet investigated in breast cancer. Here, we demonstrate that DMXL2 is overexpressed in a subset of endocrine therapy resistant breast cancer cell lines where it promotes epithelial to mesenchymal transition through hyper-activation of Notch signalling via V-ATPase dependent acidification. Following DMXL2 depletion or treatment with Bafilomycin A1, both EMT targets and Notch signalling pathway significantly decrease. We show for the first time that DMXL2 protein levels are significantly increased in ERα positive breast cancer patients that progress after endocrine therapy. Finally, we demonstrate that DMXL2 is a transmembrane protein with a potential extra-cellular domain. These findings identify DMXL2 as a novel, functional biomarker for ERα positive breast cancer.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Monica
authors.initials: M
authors.lastname: Faronato
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Van T M
authors.initials: VT
authors.lastname: Nguyen
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Darren K
authors.initials: DK
authors.lastname: Patten
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Ylenia
authors.initials: Y
authors.lastname: Lombardo
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Steel
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Naina
authors.initials: N
authors.lastname: Patel
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Woodley
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Sami
authors.initials: S
authors.lastname: Shousha
authors.affiliation: Division of Pathology, European Institute of Oncology and University of Milan, School of Medicine, London, UK.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pruneri
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Luca
authors.initials: L
authors.lastname: Magnani
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002843:Chromatin / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D046888:Tissue Array Analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; C452848:DMXL2 protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch
keywords: DMXL2; EMT; Notch; breast cancer; endocrine therapy