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

intracellular domain (NICD1). Nonetheless, the exact role levels in TNBC. Given that Tregs play a role in evading
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of NOTCH3 in BC remains unclear. A study conducted immune surveillance and are associated with increased
by Chen et al. proposed that the activation of the NICD3 tumour invasiveness and unfavourable prognoses, the
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resulted in the accumulation of p27kip1, leading to the disruption of Tregs’ function mediated by NOTCH3
arrest of cancer cell cycles in the G0/G1 phase. signalling could significantly impact on BC therapy.
Nonetheless, no study has directly examined NOTCH3
Another extensively recognised immune component
of BC is the presence of tumour-associated macrophages signalling within Tregs in the context of BC. Therefore, it is
imperative to gain a better understanding of how different
(TAMs). One study indicated that the JAG-mediated NOTCH3 ligands and receptors regulate the recruitment
NOTCH signalling in BC has been linked to the
differentiation of macrophages into TAMs within the of Tregs. Intriguingly, NOTCH3 signalling can also
TME in luminal BC patient samples. When tumour cells hinder the function of Tregs, potentially diminishing their
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and TAMs are co-cultured, it leads to the differentiation capacity for immunosuppression.
of macrophages into a predominant M2-type phenotype. 6.1. NOTCH3 and BC metastasis and chemo-sensitivity
While TAMs can exhibit both inflammatory and
immunosuppressive behaviours, in BC patient samples In terms of BC metastasis, NOTCH3 expression is notably
they are primarily linked to the immunosuppressive M2 higher in invasive cancer when compared to ductal
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subtype. This association is largely due to the elevated carcinoma in situ. In addition, the truncated isoform
secretion of macrophage colony-stimulating factors by of the Fms-related receptor tyrosine kinase 1 has been
tumour cells, which directs macrophages toward the M2 linked to enhanced BC invasiveness and was found to
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phenotype. On the other hand, in the basal subtype of be upregulated by NOTCH3. Lymphovascular emboli
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BC, NOTCH3 signalling through JAG-1 in tumour cells in human inflammatory BC have shown elevated levels
of NOTCH3 expression. When normal breast epithelial
triggers the release of crucial macrophage-activating cells were transfected with NICD3, spheroid formation
cytokines, including IL-β and CCL-2. These cytokines
facilitate the recruitment of M2-type macrophages, was observed, a phenomenon that was not seen after
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which subsequently secrete transforming growth factor-β NICD1 transfection. An exclusive elevation in NOTCH3
(TGF-β), thus activating TGF-β signalling within the expression was also observed in human BC cell lines
tumour cells. The interplay between tumour cells and following exposure to TGF-β1 released by bone marrow
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TAMs mediated by NOTCH3 signalling could also be osteoblasts. The formation of cancer cell colonies was
impeded upon treatment with an anti-TGF-β1 antibody
of significance in the development of drug resistance, and chemical inhibition of NOTCH3. Furthermore, the
although additional investigation is needed. 108
expression of NOTCH3 was linked to the presence of
The involvement of NOTCH3 in the epidermal-to- osteolytic bone lesions. 121
mesenchymal transition (EMT) in BC remains a topic of Another mechanism by which NOTCH3 can
debate. Some researchers have indicated that NOTCH3 enhance the aggressiveness of BC is through its role in
encourages tumour aggressiveness by instigating EMT, cellular metabolism. NOTCH3 activity is crucial for
while others have shown evidence that NOTCH3 inhibits the survival of metastatic BC cells resistant to hormone
EMT, for instance, by upregulating the Hippo/Yap therapy. Furthermore, it has been demonstrated to boost
pathway. It has been reported that EMT inhibition can mitochondrial activity and facilitate the transition out
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also occur through the reduction of Fos-related antigen 1 of metabolic dormancy. In tamoxifen-resistant cells,
(Fra1), an activator of the EMT process. This observation mitochondrial DNA copy number, mitochondrial
was made in human BC cells that developed resistance to antigen expression, and oxidative phosphorylation were
Adriamycin, where Fra1 was expressed at elevated levels all reduced. The decline in mitochondrial activity was
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whilst NOTCH3 was downregulated. Conversely, within reversed through IL-6 treatment, which was orchestrated
metastatic BC cells, a reduction in NOTCH3 levels resulted by NOTCH3. The critical function of NOTCH3 in
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in reduced levels of EMT-associated proteins, such as reversing the mitochondrial damage induced by tamoxifen
vimentin, fibronectin and Snail. was substantiated when IL-6 treatment proved ineffective
Previous study on animal models of allergic airway in enhancing mitochondrial activity in cells with
inflammation have shown that regulatory T-cells (Tregs), suppressed NOTCH3. Multiple studies have supported
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another prominent immune component associated with that in metastatic BC, the presence of functional NOTCH3
immune suppression, are elevated by both JAG-1 and is indispensable for IL-6 to sustain elevated levels of
JAG-2 through the involvement of mesenchymal stem carbonic anhydrase, an enzyme linked to survival in
cells. Both JAG-1 and JAG-2 exhibit elevated expression hypoxic conditions and increased invasiveness in cancer. 122
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Volume 9 Issue 3 (2025) 40 doi: 10.36922/EJMO025150095