Notch Signaling in Breast Tumor Microenvironment as Mediator of Drug Resistance

Chimento, Adele; D’Amico, Maria; Pezzi, Vincenzo; Amicis, Francesca De

doi:10.3390/ijms23116296

Cited by 16 publications

(10 citation statements)

References 140 publications

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“…It has been discovered that Notch-3 NICD is abundantly expressed in breast tissue and is linked to the prevalence of mammary gland tumors, revealing its potential as an oncogene. Several breast gland cell lines associated with breast cancer have also been shown to express Notch-1 and Notch-3 NICD, supporting the idea of their involvement in breast tumorigenesis 142 . Dysfunctional genetic variants of Notch-4 NICD have been linked to breast tumorigenesis as well.…”

Section: Clinical Investigation Into Notch Signalling Expressionmentioning

confidence: 60%

Navigating breast cancer complexity: Deciphering the cross talk of Wnt/β catenin and Notch pathways in development and diseases

Rasool,

Bhat,

Khurshid

et al. 2024

Preprint

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This study investigates miRNA impact on lung, colorectal, and epithelial cancers, emphasizing Wnt3’s role in breast tumor growth through WNT signaling and its influence on mammary stem cells. WNT pathway inactivation induces drug-insensitive, quiescent states in breast cancer stem cells, resulting in resistance to multiple drugs. Tamoxifen-resistant breast carcinoma cells activate both canonical and noncanonical WNT signaling, with Wnt3a enhancing tamoxifen resistance in ER+ carcinoma cells. The study also explores breast cancer immunotherapy, highlighting immune checkpoint blockade targeting PD-1/PD-L1 and CTLA-4 as promising avenues. Additionally, the study explores the NOTCH signaling pathways impact on cancer proliferation, apoptosis, invasion and metastasis. Elevated NOTCH receptor and ligand expression particularly in aggressive triple negative breast cancer correlate with poorer treatment outcome, serving as a predictor for adverse results in breast tumors. The review discusses the relevance of Notch signaling in therapy resistance and breast cancer recurrence. The article encapsulates therapeutic advancements targeting the Notch signaling pathway, weighing merits and demerits in the context of breast cancer treatment. Our study provides a comprehensive understanding of the complex interactions within the WNT and Notch signaling pathways in breast cancer, shedding light on potential therapeutic targets and strategies for personalized treatment. This research significantly contributes to the current body of knowledge, offering promise for improved outcomes in breast cancer patients. The findings underscore the importance of WNT and Notch signaling modulation in developing effective therapeutic interventions for breast cancer.

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Section: Clinical Investigation Into Notch Signalling Expressionmentioning

confidence: 60%

Navigating breast cancer complexity: Deciphering the cross talk of Wnt/β catenin and Notch pathways in development and diseases

Rasool,

Bhat,

Khurshid

et al. 2024

Preprint

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show abstract

“…In the cell–cell interactions analysis, we found JAG-NOTCH interactions between tumor cells and endothelial cells. The Notch pathway is involved in tumor progression through various mechanisms such as stem cell maintenance, cell proliferation, and migration/invasion [ 51 , 52 ]. These studies reported that the Notch pathway regulates many components of the TME, including immune cells, fibroblast, endothelial, and mesenchymal cells.…”

Section: Discussionmentioning

confidence: 99%

A Retrospective View of the Triple-Negative Breast Cancer Microenvironment: Novel Markers, Interactions, and Mechanisms of Tumor-Associated Components Using Public Single-Cell RNA-Seq Datasets

Kim,

Yang,

Hong

et al. 2024

Cancers

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Triple-negative breast cancer (TNBC) is a significant clinical challenge due to its aggressive nature and limited treatment options. In search of new treatment targets, not only single genes but also gene pairs involved in protein interactions, we explored the tumor microenvironment (TME) of TNBC from a retrospective point of view, using public single-cell RNA sequencing datasets. A High-resolution Cell type Annotation Tool, HiCAT, was used first to identify the cell type in 3-level taxonomies. Tumor cells were then identified based on the estimates of copy number variation. With the annotation results, differentially expressed genes were analyzed to find subtype-specific markers for each cell type, including tumor cells, fibroblast, and macrophage. Cell–cell interactions were also inferred for each cell type pair. Through integrative analysis, we could find unique TNBC markers not only for tumor cells but also for various TME components, including fibroblasts and macrophages. Specifically, twelve marker genes, including DSC2 and CDKN2A, were identified for TNBC tumor cells. Another key finding of our study was the interaction between the DSC2 and DSG2 genes among TNBC tumor cells, suggesting that they are more tightly aggregated with each other than those of other subtypes, including normal epithelial cells. The overexpression of DSC2 in TNBC and its prognostic power were verified by using METABRIC, a large bulk RNA-seq dataset with clinical information. These findings not only corroborate previous hypotheses but also lay the foundation for a new structural understanding of TNBC, as revealed through our single-cell analysis workflow.

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“…Studies have shown that Notch pathway activation is a major participant in breast cancer progression (23), therapy resistance (24) and is the pathognomonic feature in triple negative breast cancer (TNBC) (25). Notch1 has a role in maintaining CSC stemness in TNBC, and inhibiting this signal not only has an inhibitory effect on this cancer subtype but also increases its chemosensitivity (26).…”

Section: Discussionmentioning

confidence: 99%

Hydroxytyrosol, a component of olive oil for breast cancer prevention in women at high risk of cancer

Puri,

Yin,

Granados-Principal

et al. 2023

Preprint

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Background This study evaluates the effects of hydroxytyrosol (HT), a component of olive oil, on mammographic breast density reduction. We explored effects of HT on Wnt β-catenin and other pathways involved in cancer stem cell renewal, DNA repair, cell proliferation and differentiation. Methods 25mg/day oral dose of HT were given for 12 months in pre- and post-menopausal women at increased risk of breast cancer. Out of 51 patients enrolled, 41 completed the study. The annualized percent decrease in maximum mammographic volumetric breast density (Max VBD%) between baseline (BL) and end-of-treatment (EOT) was analyzed. RNA sequencing (RNA-Seq) and multiplex analysis was performed on the breast biopsies to compare the BL with EOT samples. Results Max VBD% showed a non-significant change; however, in women 60 years or older, the max VBD% decrease was significant (3.7%, p=0.0391), especially in those with high baseline mammographic density. Using RNA-Seq, 3,330 unique transcripts were identified (p<0.05). Mitotic telophase/cytokinesis, DNA damage were upregulated, whereas Wnt, Notch, and Oxidative stress-induced senescence pathways were downregulated (p<0.05). These pathways were confirmed by Nano string n counts where significant decrease in proliferative genes (RELA and CDK4), Wnt pathway (R-HSA-195721 and R-HAS-201681) were observed (p< 0.05). Conclusions Hydroxytyrosol significantly reduced breast density only in women over 60 years, especially in those with high baseline breast density. HT also reduced proliferation and affected Wnt signaling pathway. This study lays the foundation for future larger studies in exploring a natural compound with well tolerability and overall nontoxic profile for chemoprevention of breast cancer.

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Notch Signaling in Breast Tumor Microenvironment as Mediator of Drug Resistance

Cited by 16 publications

References 140 publications

Navigating breast cancer complexity: Deciphering the cross talk of Wnt/β catenin and Notch pathways in development and diseases

Navigating breast cancer complexity: Deciphering the cross talk of Wnt/β catenin and Notch pathways in development and diseases

A Retrospective View of the Triple-Negative Breast Cancer Microenvironment: Novel Markers, Interactions, and Mechanisms of Tumor-Associated Components Using Public Single-Cell RNA-Seq Datasets

Hydroxytyrosol, a component of olive oil for breast cancer prevention in women at high risk of cancer

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