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REVIEW ARTICLE

NOTCH3 signalling as a therapeutic nexus: Bridging cerebral small vessel disease and breast cancer pathophysiology

Zaw Myo Hein1 ,  Nisha Shantakumari1 ,  Muhammad Danial Che Ramli2 ,  Usman Jaffer3 ,  Hafizah Abdul Hamid4 ,  Che Mohd Nasril Che Mohd Nassir5*
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1 Department of Basic Medical Sciences, College of Medicine, Ajman University, Ajman, United Arab Emirates
2 Department of Diagnostic and Allied Health Science, Faculty of Health and Life Sciences, Management and Science University, Shah Alam, Selangor, Malaysia
3 Department of Human Science, Kulliyyah of Islamic Revealed Knowledge and Human Sciences, International Islamic University Malaysia, Kuala Lumpur, Malaysia
4 Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
5 Department of Anatomy and Physiology, School of Basic Medical Sciences, Faculty of Medicine, Universiti Sultan Zainal Abidin, Kuala Terengganu, Terengganu, Malaysia
EJMO, 025150095 https://doi.org/10.36922/EJMO025150095
Received: 8 April 2025 | Revised: 24 April 2025 | Accepted: 8 May 2025 | Published online: 30 May 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

The neurogenic locus notch homolog protein 3 (NOTCH3), is central in both vasculogenesis and oncogenesis and, therefore, has been considered an important factor in the development of cerebral small vessel disease (CSVD) and breast cancer (BC). Pathogenic mutations of NOTCH3 induce vascular smooth muscle cell degeneration, microvascular dysfunction and neurovascular damage in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is a genetic cause of CSVD. Meanwhile, NOTCH3 aberrant signalling in BC promotes tumour progression, metastasis and chemoresistance, especially in aggressive subtypes, such as triple-negative BC. A growing body of evidence points to a common molecular pathway whereby NOTCH3 dysregulation mediates vascular and tumour pathologies, thus providing an important link between these conditions. This narrative review synthesises current insights into the dual role of NOTCH3, focusing on translational relevance as a therapeutic target. Targeting NOTCH3 may mitigate vascular damage in CSVD and simultaneously inhibit tumour progression and metastasis in BC. The review further discusses NOTCH3 as a biomarker for early diagnosis and risk stratification, besides novel therapeutic strategies involving γ-secretase inhibitors and monoclonal antibodies. Future directions include studies into the ligand-independent functions of NOTCH3, its role within the tumour microenvironment, and the development of therapies with dual-action potential. This review discusses, for the 1st time, common mechanisms between CSVD and BC, thereby opening new avenues for therapies that could effectively target both conditions. By translating these laboratory findings into clinical applications, this approach aims to improve outcomes for patients affected by these devastating disorders.

Keywords
Cerebral small vessel disease
Breast cancer
Neurogenic locus notch homolog protein 3
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy
Tumor
Funding
Financial support for the article processing charge was provided by Ajman University, UAE.
Conflict of interest
The authors declare they have no competing interests.
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Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing
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