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Eurasian Journal of
Medicine and Oncology NOTCH3 in CSVD and breast cancer

NOTCH3 can enhance chemo-sensitivity in participates in the regulation of satellite cells, which are
doxorubicin-resistant BC by negatively regulating stem cells responsible for the repair of skeletal muscle.
Fra1, a critical factor in the EMT of BC cell lines. 80,123 In A recent study demonstrated that mice lacking NOTCH3
doxorubicin-resistant BC cells, Fra1 was notably over- exhibited significantly greater muscle growth than their
expressed while NOTCH3 was under-expressed. This wild-type counterparts following repeated injuries, which
resistance was attributed to the EMT induced by Fra1. It was attributed to the increased proliferation of activated
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was possible to induce Adriamycin chemo-resistance in satellite cells. In contrast, NOTCH1 has been associated
initially chemo-sensitive cells by suppressing NOTCH3 with promoting satellite cell activation and proliferation. 129
signalling. Apart from that, the stromal cells can also
80
further enhance chemo-resistance by stimulating the 7.1. NOTCH3 gene aberration and risk for ischemic
expression of NOTCH3 in BC cells, an effect that can stroke
be counteracted with NOTCH3 siRNA or a γ-secretase The exact pathophysiological mechanisms responsible
inhibitor (GSI). Another mechanism by which cancer for ischemic stroke and its various subtypes remain
110
cells resist treatment is through a state of tumour dormancy. incompletely understood. A combination of genetic and
Activation of the NOTCH3 pathway induces cell cycle environmental factors probably contributes to the onset and
arrest at the G0/G1 phase and promotes the expression progression of the condition. The NOTCH3 gene is in the
130
of DNp63a, Mix1 and Hes1 proteins, which encourage 19p13.12 region, spanning from 15,159,633 base pairs to
cellular quiescence. 124 15,200,981 base pairs. It comprises 33 exons and 32 introns
and encodes a protein consisting of 2,321 amino acids,
Given the constrained effectiveness of immunotherapy 131
directed solely at tumour cells in BC, it becomes crucial which plays a critical role in neuronal development. The
NOTCH3 gene variants, rs1044009 (g.45022C > T, c.6668C
to comprehend the regulatory function of NOTCH3 > T, p. Ala2223Val), and rs3815188 (g.13568C > T, c.303C
signalling in the interactions between cancer cells and > T, p. Thr101=), correspond to a missense mutation and
immune cells within the TME across various subtypes of a synonymous variant, respectively. Both polymorphisms
BC. This understanding can facilitate the identification of are situated within the intracellular DUF3454 domain of
more effective drug targets involving NOTCH3 signalling the protein, and they have a direct impact on the signal
and immune cells. transduction activity of NOTCH3. However, NOTCH3

7. NOTCH3 and the brain rs1043994 (g.13949A > G, c.606A > G, p. Ala202=) is a
benign point mutation or synonymous variant situated
A previous study reported that adult mice with NOTCH3 in the conserved protein family of the calcium-binding
deficiency exhibit ongoing progressive symptoms in the endothelial growth factor (EGF)-like domain within the
vasculature of the brain and retina, stemming from VSMC NOTCH3 protein. 132
degeneration and loss through apoptosis. 125 This leads to
a breakdown in vessel integrity, causing haemorrhaging Certain mutations in the NOTCH3 gene have been
and impairing the functionality of the blood–brain barrier documented as a direct cause of CADASIL, an autosomal
dominant disorder affecting cerebral small penetrating
(BBB). Furthermore, the expression of NOTCH3 in vessels. It presents typical clinical symptoms such as
VSMCs contributes to the regulation of vascular tone and migraine with aura, recurrent ischemic strokes in early to
flow-mediated dilation in both cerebral and tail resistance middle adulthood, apathy, neuropsychological symptoms
arteries in mice. Moreover, the functions of NOTCH3 and cognitive impairment that advances to dementia.
125
132
may extend beyond vascular roles, whereby recent research The details on NOTCH3 gene aberration and its roles in
has reported its involvement in neuronal stem cells and ischemic strokes and CSVD will be discussed in the later
neuronal differentiation. 126 section.
The subependymal zone serves as a crucial stem
cell niche within the adult mammalian brain, housing 7.2. NOTCH3 and inherited cause of CSVD
both active and dormant stem cell populations. There However, as far back as the 1970s, literature documented
is a distinct functional difference between NOTCH1 families who, despite lacking typical vascular risk factors,
and NOTCH3 in the regulation of these populations. In exhibited a heightened susceptibility to CSVD. Studies
mouse model studies, NOTCH1 is expressed in active reported cases of families in which multiple-infarct
stem cells, stimulating their proliferation. On the other dementia afflicted individuals in a manner consistent with
hand, NOTCH3 is primarily expressed in quiescent stem autosomal-dominant inheritance. 133,134 The prevalence of
cells, and its role is essential for maintaining these cells by deep white-matter lesions in these individuals indicated
inhibiting their proliferation. Apart from that, NOTCH3 that they were likely influenced by a genetic factor causing
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Volume 9 Issue 3 (2025) 41 doi: 10.36922/EJMO025150095