Page 40 - EJMO-9-3

Eurasian Journal of Medicine

and Oncology

REVIEW ARTICLE
NOTCH3 signalling as a therapeutic

nexus: Bridging cerebral small vessel disease and
breast cancer pathophysiology

Zaw Myo Hein 1 , Nisha Shantakumari 1 , Muhammad Danial Che Ramli 2 ,
5
Usman Jaffer 3 , Hafizah Abdul Hamid 4 , and Che Mohd Nasril Che Mohd Nassir *
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

Abstract

The neurogenic locus notch homolog protein 3 (NOTCH3), is central in both
vasculogenesis and oncogenesis and, therefore, has been considered an important
*Corresponding author: factor in the development of cerebral small vessel disease (CSVD) and breast
Che Mohd Nasril Che Mohd Nassir
(nassrilnassir@unisza.edu.my) cancer (BC). Pathogenic mutations of NOTCH3 induce vascular smooth muscle cell
degeneration, microvascular dysfunction and neurovascular damage in cerebral
Citation: Hein ZM,
Shantakumari N, Ramli MDC, Jaffer autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy
U, Hamid HA, Nassir CMNCM. (CADASIL), which is a genetic cause of CSVD. Meanwhile, NOTCH3 aberrant signalling
NOTCH3 signalling as a therapeutic in BC promotes tumour progression, metastasis and chemoresistance, especially in
nexus: Bridging cerebral small aggressive subtypes, such as triple-negative BC. A growing body of evidence points
vessel disease and breast cancer
pathophysiology. Eurasian J Med to a common molecular pathway whereby NOTCH3 dysregulation mediates vascular
Oncol. 2025;9(3):32-51. and tumour pathologies, thus providing an important link between these conditions.
doi: 10.36922/EJMO025150095 This narrative review synthesises current insights into the dual role of NOTCH3,
Received: April 8, 2025 focusing on translational relevance as a therapeutic target. Targeting NOTCH3 may
mitigate vascular damage in CSVD and simultaneously inhibit tumour progression
Revised: April 24, 2025 and metastasis in BC. The review further discusses NOTCH3 as a biomarker for early
Accepted: May 8, 2025 diagnosis and risk stratification, besides novel therapeutic strategies involving
γ-secretase inhibitors and monoclonal antibodies. Future directions include studies
Published online: May 30, 2025
into the ligand-independent functions of NOTCH3, its role within the tumour
Copyright: © 2025 Author(s). microenvironment, and the development of therapies with dual-action potential. This
This is an Open-Access article st
distributed under the terms of the review discusses, for the 1 time, common mechanisms between CSVD and BC, thereby
Creative Commons Attribution opening new avenues for therapies that could effectively target both conditions. By
License, permitting distribution, translating these laboratory findings into clinical applications, this approach aims to
and reproduction in any medium, improve outcomes for patients affected by these devastating disorders.
provided the original work is
properly cited.
Publisher’s Note: AccScience Keywords: Cerebral small vessel disease; Breast cancer; Neurogenic locus notch homolog
Publishing remains neutral with protein 3; Cerebral autosomal-dominant arteriopathy with subcortical infarcts and
regard to jurisdictional claims in
published maps and institutional leukoencephalopathy; Tumor
affiliations.

Volume 9 Issue 3 (2025) 32 doi: 10.36922/EJMO025150095