DMXL2 drives epithelial to mesenchymal transition in hormonal therapy resistant breast cancer through Notch hyper-activation
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Monica Faronato1, Van T.M. Nguyen1, Darren K. Patten1, Ylenia Lombardo1, Jennifer H. Steel1, Naina Patel1, Laura Woodley1, Sami Shousha1, Giancarlo Pruneri2, R. Charles Coombes1, Luca Magnani1
1Department of Surgery and Cancer, Imperial College London, London, UK
2Division of Pathology, European Institute of Oncology and University of Milan, School of Medicine, London, UK
Luca Magnani, e-mail: firstname.lastname@example.org
Keywords: DMXL2, breast cancer, Notch, endocrine therapy, EMT
Received: March 23, 2015 Accepted: May 22, 2015 Published: June 04, 2015
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.
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