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

surround arterial vessels. Moreover, in vitro studies Moreover, one study reported that mutations in the NRR
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suggest that the expression of JAG-1 in endothelial cells and PEST domains of the NOTCH3 gene could lead to
triggers the activation of NOTCH3 in VSMCs, and this NOTCH3 activation, characterised as gain-of-function or
process forms an auto-regulatory loop that sustains the activating mutations. These mutations have been observed
expression of NOTCH3 in VSMCs. In this process, in human T-ALL. 103
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a pivotal downstream effector is the platelet-derived An important function of NOTCH3 is the preservation
growth factor (PDGF) signalling pathway, and NOTCH3 of cancer stem cell (CSC) stemness. CSCs, a subset of self-
activation leads to the upregulation of PDGF. 73 renewing cells possessing strong tumourigenic potential,
Additional research has demonstrated that NOTCH3 are known to be stimulated by NOTCH3 signalling in
plays earlier roles within the VSMC lineage, although these various cancer types, thereby contributing to cancer
functions may be concealed by the partial redundancy progression through intricate mechanisms. Another
with other NOTCH homologues. In one animal study on significant aspect of NOTCH3 signalling is its ability to
zebrafish, researchers have found that Notch2 and Notch3 promote resistance to multiple types of chemotherapeutic
cooperate to govern the embryonic production of both drugs, such as platinum agents, doxorubicin, epidermal
mesoderm-derived and neural crest-derived mural cells, growth factor receptor (EGFR)–tyrosine kinase inhibitors,
which serve as precursors for VSMCs. This was supported taxanes, and gemcitabine. It’s important to highlight that
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by a later study that revealed a comparable redundancy in the support of CSC activity by NOTCH3 is also implicated
mice models, as double mutants lacking both NOTCH2 and in the mechanisms of tumour chemo-resistance,
NOTCH3 are embryonically lethal, and this is associated angiogenesis, and metastasis. 36,104,105 These underscore the
with a profound reduction in VSMCs and the presence of pivotal role of NOTCH3 signalling in cancer.
vascular abnormalities. Nonetheless, additional research
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employing primary cell cultures has unveiled distinctive 6. Roles of NOTCH3 in BC
roles for NOTCH2 and NOTCH3 within the VSMCs. For In the context of BC, NOTCH3 typically functions as an
example, NOTCH2 exerts an inhibitory effect on VSMC oncogene, with a few exceptions. Notably, NOTCH3 has
proliferation, whereas NOTCH3 facilitates proliferation been shown to induce the development of mammary
6
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and serves as a protective factor against VSMC apoptosis. tumours in transgenic mice. Among BC cell lines,
The functional overlap and interactions between various NOTCH3 signalling remains persistently active, and when
NOTCH proteins are therefore intricate and greatly compared to other NOTCH receptors, its activity alone is
context-dependent. adequate to drive tumour growth both in vitro and in vivo.
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Recently, there has been an acknowledgement of the role
5.2. NOTCH3 and cancer of juxtacrine NOTCH signalling between tumour cells and
While the primary role of NOTCH appears to be the distinct cell types within the tumour microenvironment
regulation of vasculogenesis, where its dysregulation has (TME). 106
been associated with various vascular disorders, it can The communication between cancer cells and the
also exhibit tumour-suppressing or oncogenic functions. TME, which includes both juxtacrine and paracrine
Numerous studies have demonstrated the common signalling, holds significance in the development of novel
occurrence of aberrantly elevated NOTCH3 expression targeted therapies for BC progression and addressing
in human cancer tissues. Table 2 summarises the tumour- drug resistance. Certainly, the activation of NOTCH3 in
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suppressive and oncogenic roles of human NOTCH3. tumour cells stimulates the release of various soluble factors
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The overexpression of NOTCH3 in cancer tissues is that can exert paracrine effects on cells within the TME.
associated with various clinicopathological characteristics, These effects extend to immune and stromal cells, including
including larger tumour size, advanced tumour-node- cancer-associated fibroblasts (CAFs) and endothelial cells.
metastasis stage, higher pathological grade, tumour However, it’s important to highlight that CAFs can also
metastasis, and an unfavourable prognosis. This is reflected enhance NOTCH3 signalling and contribute to resistance
in diminished disease-free survival, progression-free by secreting multiple pro-inflammatory cytokines and
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survival, relapse-free survival, and overall survival among chemokines. 109,110 Indeed, Studebaker et al. observed that
cancer patients. 100,101 The predominant cause for NOTCH3 BC CAFs activate NOTCH3 through the secretion of IL-6.
overexpression in cancer is genetic alterations within the Apart from that, a previous study by Yamaguchi
NOTCH3 gene. According to the Cancer Genome Atlas, et al. highlighted the significance of NOTCH3
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the NOTCH3 gene was modified in 5% of cancer samples, signalling when compared to other NOTCH family
primarily through mutations and gene amplification. members. They revealed that reducing NOTCH3
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Volume 9 Issue 3 (2025) 38 doi: 10.36922/EJMO025150095