Page 41 - EJMO-9-3

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

1. Introduction among NOTCH3 signaling, CSVD and BC. Across
exploring the common mechanical foundations of these
Breast cancer (BC) and stroke are two different medical illnesses, we hope to uncover new understandings of their
disorders, each with unique pathophysiological causes. relationship. These disclosures could lead to the creation of
Recent discoveries suggest a possible connection between novel preventive and therapeutic approaches, which would
these two unconnected entities, identifying the roles of be an example of ‘killing two birds with one stone’ in the
1,2
neurogenic locus notch homolog protein 3 (NOTCH3) fight against these powerful enemies.
signalling as important participants in both illnesses.

One member of the NOTCH family that has become 2. BC
important in both oncogenesis and vasculogenesis is BC is an array of distinguished malignancies that occur
NOTCH3. Variations in the NOTCH3 gene have been within the mammary glands. Indications of BC can
9
linked to several cardio- and cerebral-vascular diseases, encompass a breast lump, alterations in breast contour, skin
such as cerebral small vessel disease (CSVD), which is dimpling, nipple discharge, inverted nipple (turns inward),
a precursor to stroke and is characterised by cerebral and/or the presence of a red or scaly skin patch. 10,11 In
autosomal-dominant arteriopathy with subcortical addition, individuals with the disease or tumours that have
infarcts and leukoencephalopathy (CADASIL). The metastasised to distant sites may experience symptoms
3
pathological hallmark of CSVD is the accumulation of such as bone pain, difficulty in breathing, enlarged lymph
NOTCH3 extracellular domain within small penetrating nodes, and/or jaundice. Factors that increase the risk of
12
arteries, which is noteworthy. Despite CSVD is often developing BC encompass a sedentary lifestyle, obesity,
4
silent, many affected individuals remain asymptomatic. alcohol consumption, early onset of menstruation, ageing,
Their manifestation is frequently unintentionally detected delayed or absent childbearing, hormone replacement
during normal magnetic resonance imaging (MRI) brain therapy during menopause, exposure to ionising radiation,
scans, showing distinctive cerebral white matter lesions. 5 a prior BC diagnosis and a family history of the disease. 13
Moreover, pre-clinical studies have revealed that 2.1. BC epidemiology and present trends
NOTCH3 plays a dual role in BC, contributing to both
tumor development and metastatic progression. BC is the second most common cause of cancer-related
6,7
14
Alarmingly, increased cancer invasiveness, partly mediated mortality in women globally. The World Health
by the development of lymphovascular emboli, is associated Organization reported that in 2020, BC was diagnosed in
8
with elevated NOTCH3 expression in inflammatory BC. 2.3 million women worldwide, resulting in 685,000 fatalities.
These results are further supported by observations that By the end of 2020, there were 7.8 million women who had
hypercoagulation and vascular impairment related to received a BC diagnosis within the past 5 years, solidifying its
cancer are associated with a higher risk of stroke and that status as the most widespread cancer globally. Moreover, BC
stroke-related death is more common in BC patients than affects women of all ages in every country after they reach
in non-cancer patients. 9 puberty, with higher incidence rates in later life. Alarmingly,
around 0.5 – 1% of BC cases are observed in males. 15
Given the ageing global population and the increasing
Moreover, BC has experienced a significant rise in both
incidence of both CSVD and BC, the clinical overlap the number of cases and fatalities in the past 30 years.
between these conditions is of growing interest. CSVD
contributes significantly to ischemic stroke, a leading cause Between 1990 and 2016, BC cases more than doubled in
of death in cancer patients, and the underlying shared 60 out of 102 countries, including Afghanistan, Argentina,
molecular mechanisms involving NOTCH3 signalling Brazil and the Philippines. Simultaneously, BC-related
may suggest an urgent need for integrative research. deaths also doubled in 43 out of 102 countries, including
16
Uncovering these connections holds the potential to Libya, Paraguay, Saudi Arabia and Yemen. It has been
transform clinical approaches by identifying shared suggested that according to the projections for the year
2030, there will be approximately 2.7 million new cases of
therapeutic targets and improving outcomes in patients BC diagnosed globally each year, with around 0.87 million
at the intersection of these pathologies. The intersection annual deaths. Moreover, the incidence of BC in low- and
17
of these research avenues demands a reassessment of the middle-income countries is anticipated to rise even more,
clinical environment, where the symptomatology of BC primarily because of the increasing adoption of Western
and CSVD may counterintuitively resemble one another, lifestyles, which include the previously mentioned risk
ultimately predisposing individuals to ischemic stroke. factors. In addition, improved cancer registration and
Thus, the purpose of this narrative review is to compile diagnostic capabilities also contribute to the observed
the body of knowledge clarifying the dynamic interactions increase in reported cases. 18

Volume 9 Issue 3 (2025) 33 doi: 10.36922/EJMO025150095