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Updated: Apr 9, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
DMXL2 drives epithelial to mesenchymal transition in hormonal therapy resistant breast cancer through Notch
Monica Faronato1, Van T M Nguyen1, Darren K Patten1
1Department of Surgery and Cancer, Imperial College London, London, UK.
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.
Insights
DMXL2, a novel protein, is overexpressed in endocrine therapy-resistant breast cancer, promoting resistance by activating Notch signaling. Elevated DMXL2 indicates poor prognosis and serves as a potential biomarker for ERα-positive breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Endocrine therapy resistance in estrogen receptor α (ERα) positive breast cancer is a significant clinical challenge.
- Notch signaling is implicated in breast cancer progression and resistance to endocrine therapy.
- Identifying reliable biomarkers for Notch activity is crucial due to the complexity of the signaling pathway.
Purpose of the Study:
- To investigate the role of DMXL2, a novel Notch signaling regulator, in endocrine therapy-resistant ERα positive breast cancer.
- To determine if DMXL2 can serve as a biomarker for treatment resistance.
- To elucidate the mechanism by which DMXL2 influences endocrine therapy resistance.
Main Methods:
- Overexpression analysis of DMXL2 in endocrine therapy-resistant breast cancer cell lines.
- Assessment of epithelial to mesenchymal transition (EMT) and Notch signaling pathway activity.
- Investigation of DMXL2's effect on Notch signaling via V-ATPase dependent acidification.
- Analysis of DMXL2 protein levels in patient samples with ERα positive breast cancer progressing after endocrine therapy.
- Characterization of DMXL2 as a transmembrane protein.
Main Results:
- DMXL2 is overexpressed in a subset of endocrine therapy-resistant breast cancer cell lines.
- DMXL2 promotes EMT and hyper-activates Notch signaling through V-ATPase dependent acidification.
- DMXL2 depletion or V-ATPase inhibition (Bafilomycin A1) reduces EMT and Notch signaling.
- DMXL2 protein levels are significantly increased in ERα positive breast cancer patients progressing after endocrine therapy.
- DMXL2 is identified as a transmembrane protein.
Conclusions:
- DMXL2 is a novel regulator of Notch signaling and a key driver of endocrine therapy resistance in ERα positive breast cancer.
- DMXL2 promotes resistance by enhancing Notch signaling and driving EMT.
- Elevated DMXL2 levels in patients indicate progression after endocrine therapy.
- DMXL2 represents a promising novel biomarker for ERα positive breast cancer, particularly in cases of endocrine therapy resistance.
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