Page 42 - EJMO-9-3

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

2.2. Genetics of BC: Present updates we will discuss the precursor for ischemic stroke, CSVD

While BC research has predominantly focused on and its relation to BC.
understanding the molecular mechanisms behind 3. CSVD
tumourigenesis, metastatic spread to distant organs
following the surgical removal of the primary tumour CSVD is responsible for approximately 25% of ischemic
remains a significant factor contributing to unfavourable strokes, most intracerebral haemorrhages in individuals
outcomes. Hence, it is crucial to gain a deeper over the age of 65, as well as the primary cause of vascular
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comprehension of the molecular mechanism that drives dementia. A recent study also linked CSVD with vascular
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cancer cell seeding and the development of metastases. Parkinsonism. In addition, it is linked to issues with
This knowledge is beneficial for the development of novel mobility, gait, neurobehavioural functions and mood
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therapies specifically targeting breast tumour metastasis- disorders. The pathophysiological foundation of CSVD
initiating cells, with the goal of halting the advancement encompasses alterations in the structure and function of
of the tumour. the microvasculature within the deep subcortical regions.
These alterations primarily affect arteries, including
Despite only about 5 – 10% of BC cases having a genetic
basis, multiple genetic mutations have been identified as tributaries of the middle cerebral artery, and arterioles,
resulting in phenomena, such as fibrinolysis, lipohyalinosis,
strongly linked to an elevated risk of developing BC. Two 39,40
prominent genes with a significant penetrance, BRCA1 necrosis and microthrombosis.
(located on chromosome 17) and BRCA2 (situated on CSVD is a condition that becomes increasingly
chromosome 13), are primarily associated with an elevated prevalent with age and is frequently encountered as
risk of BC development. The mutations in these genes an incidental discovery during neuroimaging. This
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are typically inherited through an autosomal dominant condition is frequently underestimated by healthcare
pattern, but sporadic mutations are also frequently professionals because of its covert (silent) nature, as it
documented. Additional BC genes with significant often presents without symptoms. Clinically, it commonly
penetrance, such as TP53, CDH1, PTEN and STK11, have presents with subtle but progressive symptoms such as
also been reported. 21-24 In addition to the heightened risk forgetfulness, depression, slowed thinking, balance issues,
of BC, individuals with these mutations are also at an and urinary urgency. Present neuroimaging indicators
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increased susceptibility to ovarian cancer. (or manifestation) of CSVD based on the Standards
In addition, genetic predisposition plays a critical for Reporting Vascular Changes on Neuroimaging
role in a subset of BC cases, particularly those with early 2 encompass recent small subcortical infarcts, white
onset or strong family history. While 5 – 10% of BCs are matter hyperintensities (WMHs) of presumed vascular
hereditary, several high- and moderate-penetrance genes origin, lacunar infarcts (of presumed vascular origin),
significantly elevate the associated risk. 20,25 BRCA1 and enlarged perivascular spaces, cerebral microbleeds,
BRCA2 mutations remain the most studied, with high cortical superficial siderosis, brain atrophy and cortical
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lifetime risks for BC and ovarian cancer. Other key genes, cerebral microinfarcts. Frequent cardio-cerebrovascular
such as TP53, PALB2, CHEK2 and ATM influence tumour risk factors for sporadic CSVD, including ageing, type 2
suppression and DNA repair pathways. These mutations diabetes, hypertension, smoking and dyslipidaemia,
typically follow autosomal dominant inheritance patterns. elevate the risk of pathological alterations in arteries and
Table 1 summarises the most clinically relevant genes, arterioles, potentially resulting in vessel blockage, which
their functions and associated cancer risks. in turn leads to the development of arteriosclerosis and
arteriolosclerosis. 40
In addition to genes related to BC, NOTCH receptors
have been reported to be likely to exert distinct regulatory Several aetiopathogenic classifications have been
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effects on BC cells. Therefore, it is crucial to define the proposed for CSVD. Nevertheless, the most widely
specific functional roles of individual NOTCH receptors acknowledged categories of CSVD include amyloidal
in propelling tumour advancement. Later in this narrative CSVD (e.g., sporadic and hereditary cerebral amyloid
review, we provide evidence that the expression of angiopathy) and non-amyloid CSVD, which encompasses
NOTCH3 is associated with the pathogenesis of cancer age-related and small vessel disease related to vascular risk
cell dissemination and the progression of BC metastases. factors (such as arteriolosclerosis and ageing). Meanwhile,
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Moreover, there is an increasing body of evidence the less prevalent categories of CSVD encompass inherited
suggesting that BC can lead to the onset and progression of or genetic (monogenic) forms, which exhibit distinct
ischemic stroke, and BC is currently being referred to as a characteristics separate from cerebral amyloid angiopathy.
risk factor for stroke and its subtypes. In the next section, Examples include Fabry’s disease and CADASIL, as well

Volume 9 Issue 3 (2025) 34 doi: 10.36922/EJMO025150095