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

in the degeneration of VSMCs and the formation of boundaries and significantly improve outcomes for patients
GOM, a hallmark of CADASIL. These pathophysiological affected by both CSVD and BC. Despite the promising
changes disrupt vascular integrity, contributing to the role of NOTCH3 as a therapeutic target, several challenges
clinical manifestations of CADASIL, including migraines, must be addressed to enable clinical translation. One major
recurrent strokes, cognitive decline and psychiatric concern is the off-target effects, particularly when using
disturbances. non-selective agents, such as GSIs, which affect multiple
In BC, NOTCH3 signalling has been implicated in NOTCH receptors and may lead to gastrointestinal
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tumour growth, metastasis and chemo-resistance. Notably, and immunological side effects. Furthermore, tissue-
studies have demonstrated that IL-6-induced NOTCH3 specific variability in NOTCH3 expression complicates
activation promotes mitochondrial recovery in tamoxifen- the prediction of therapeutic responses and raises the risk
resistant BC cells, enabling the transition out of metabolic of unintended impacts on normal vascular or immune
dormancy and enhancing survival under hypoxic stress. function. Ensuring selectivity and safety in targeting
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Elevated NOTCH3 expression has been associated with NOTCH3, especially in the context of long-term treatment,
increased invasiveness and higher metastatic potential, is critical and warrants the development of more refined,
particularly in TNBC. Furthermore, NOTCH3 plays a receptor-specific strategies and delivery systems. In
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critical role in maintaining CSC properties, facilitating summary, the exploration of NOTCH3 signalling as a
EMT, and remodelling the TME through its interaction common link between CADASIL and BC underscores the
with TAMs and cytokines such as IL-6 and TGF-β. 108,115 The importance of integrated research approaches that consider
convergence of these pathomechanisms suggests a shared the multifaceted roles of key molecular players in disease
pathway that may underline both CSVD and BC. This dual pathogenesis. This comprehensive understanding could
role of NOTCH3 in vascular and oncogenic processes lead to innovative strategies for prevention, diagnosis, and
opens new avenues for therapeutic interventions targeting treatment, ultimately benefiting patients affected by these
this signalling pathway. By inhibiting aberrant NOTCH3 debilitating conditions.
activity, it may be possible to mitigate the vascular damage 9. Conclusion
seen in CADASIL and suppress tumour progression and
metastasis in BC. The intricate role of NOTCH3 in both CSVD and BC
underscores its significance as a shared molecular driver
Future research should prioritise elucidating the of vascular degeneration and tumour progression. This
molecular mechanisms of ligand-independent NOTCH3 review highlights how aberrant NOTCH3 signalling
signalling, which remains poorly understood but is contributes to VSMC dysfunction and white matter
increasingly recognised as relevant in both normal damage in CSVD, while simultaneously promoting
physiology and disease states. Studies investigating the proliferation, chemo-resistance, and immune evasion
structural instability of NOTCH3’s NRR and its role in in BC. These insights position NOTCH3 as a promising
spontaneous receptor activation could uncover novel dual-purpose therapeutic target with potential benefits
regulatory checkpoints. Furthermore, the role of NOTCH3 across neurovascular and oncologic domains. However,
within the TME, particularly its crosstalk with CAFs, this synthesis also reveals several limitations and gaps in
TAMs and Tregs, warrants further exploration to identify present knowledge. Notably, direct mechanistic studies
immunomodulatory functions that contribute to tumour that experimentally link NOTCH3 signalling between
aggressiveness and resistance. CSVD and BC are limited. The biological relevance
Therapeutically, targeting NOTCH3 offers a promising of ligand-independent NOTCH3 activation remains
dual-action approach. Strategies under development incompletely understood, as does the precise role of
include GSIs, which block NOTCH receptor cleavage and NOTCH3 in mediating immune-tumour interactions.
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downstream signalling, monoclonal antibodies specific Furthermore, while pre-clinical models suggest promising
to NOTCH3 or its ligands, such as DLL4 and JAG1, and avenues for targeted therapies, the clinical translation of
selective NOTCH3 inhibitors. These agents may be used NOTCH3 inhibitors requires caution due to potential off-
alone or in combination with conventional therapies to target effects and tissue-specific variability. In conclusion,
address vascular degeneration in CSVD and metastatic the convergence of NOTCH3 signalling in CSVD and
progression in BC. Pre-clinical models and early-phase trials BC represents both a scientific opportunity and a clinical
should focus on optimising dosage, minimising off-target challenge. Future studies should prioritise mechanistic
effects, and assessing tissue-specific responses. Ultimately, elucidation, therapeutic refinement and cross-disciplinary
advancing these research directions could lead to integrated collaboration to fully unlock the translational potential of
therapeutic strategies that transcend traditional disease targeting this signalling axis.

Volume 9 Issue 3 (2025) 44 doi: 10.36922/EJMO025150095