Page 47 - EJMO-9-3

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

Table 2. Tumor-suppressive and oncogenic roles of human NOTCH3
Type of cancer Clinicopathological features
Breast cancer • In TNBC, NOTCH3 amplifications are more frequently observed than mutations. 77
• In TNBC, mutations have been observed within the PEST domain, which plays a role in negatively regulating gene
expression. 78
• NOTCH3 is linked to increased invasiveness and a higher rate of metastasis in breast cancer. 79
• NOTCH3 is connected to the development of chemoresistance. 80
• NOTCH3 can enhance chemo-sensitivity in doxorubicin-resistant breast cancer. 80
Colorectal cancer • NOTCH3 is frequently found to be expressed at markedly elevated levels compared to its expression in normal tissue. 81
• NOTCH3 is linked to the invasiveness and metastasis of the tumour. 82
• NOTCH3 is connected to chemo-resistance and leads to poorer clinical outcomes. 83
Haemangioma • The expression of NOTCH3 is increased in stem cells of infantile hemangioma. 84
Hepatocellular carcinoma • NOTCH3 is linked to the invasiveness and metastasis of the tumour. 85
• NOTCH3 expression is markedly elevated (especially in larger tumours) compared to its expression in normal tissue. 86
Nasopharyngeal • Knocking down the expression of NOTCH3 in nasopharyngeal carcinoma enhanced the sensitivity to cisplatin
carcinoma chemotherapy. 87
Non-small cell lung cancer • 40% of non-small cell lung cancers had NOTCH3 overexpression. 88
• NOTCH3 suppressed apoptosis and reduced cell proliferation. 88
• NOTCH3 is linked to the invasiveness and metastasis of the tumour. 89
• NOTCH3 is connected to radiotherapy resistance, and chemo-resistance and leads to poorer clinical outcomes. 90
Ovarian cancer • The expression NOTCH3 is notably elevated in ovarian cancer when compared to normal ovaries or benign ovarian
tumours. 91
• The expression of NOTCH3 is linked to a higher tumour grade, lymph node, and distant metastasis, as well as a more
advanced clinical stage. 91
• NOTCH3 overexpression is linked to tumour recurrence and a higher mortality rate. 92
• Stimulating the NOTCH3 intracellular domain resulted in the accumulation of p27kip1, causing cancer cells to arrest in
the G0/G1 phase of the cell cycle. 93
Prostatic adenocarcinoma • The expression of NOTCH3 is positively associated with the Gleason score, and overexpression of NOTCH3 is observed
in prostate cancers with a high risk for metastasis. 94,95
• NOTCH3 is connected to chemo-resistance. 95
Squamous cell cancer • The expression of NOTCH3 is notably elevated in comparison with normal cells. 96
• NOTCH3 is linked to the aggressiveness of oesophageal squamous cell carcinoma and resistance to 5-fluorouracil
chemotherapy. 97
T-cell acute lymphoblastic • The activation of NOTCH3 signalling is connected to cancer cell survival and proliferation. 98
leukaemia (T-ALL) • Knockdown of NOTCH3 resulted in reduced MKP-1 levels, ultimately causing decreased tumourigenicity and an increase
in apoptosis in T-ALL. 99
Abbreviations: TNBC: Triple-negative breast cancer; MKP-1: Mitogen-activated protein kinase phosphatase 1; T-ALL: T-cell acute lymphoblastic
leukaemia.

expression significantly inhibited growth and stimulated suggests that CAFs can engage in crosstalk with cancer
apoptosis in receptor tyrosine-protein kinase (ErbB2)- cells through a CCL-2/NOTCH1 axis. 113
negative tumour cell lines. Interestingly, this effect was In addition, NOTCH3 activation has been observed in
not seen in ErbB2-positive tumour cells. Conversely, a human xenograft model of inflammatory BC through
silencing NOTCH1 using small interfering (siRNA) various methods, including real-time quantitative
did not hinder the proliferation of either ErbB2- reverse transcription polymerase chain reaction, western
positive or ErbB2-negative cell lines. Nonetheless, one blotting, and immunohistochemistry. In triple-negative
114
study demonstrated that CAFs can produce substantial BC (TNBC), NOTCH3 aberrations, specifically the
amounts of the chemokine (C-C motif) ligand 2 (CCL- amplifications of NOTCH3, are more frequently observed
2). This chemokine, in turn, can regulate the CSC compared to mutations. When mutations do occur,
109
phenotype and influence NOTCH1 expression in BC they tend to affect the PEST domain, which is generally
cells. Similarly, in a xenograft model where fibroblasts associated with the negative regulation of gene expression.
77
and BC cells were co-transplanted into NOD/SCID/ Moreover, among the TNBC samples, 34% of the tumours
IL-2Rg-null mice, the elimination of CCL-2 significantly tested positive for the NOTCH3 intracellular domain
reduced tumourigenesis and NOTCH1 expression. This (NICD3), whereas only 4% were positive for the NOTCH1

Volume 9 Issue 3 (2025) 39 doi: 10.36922/EJMO025150095