scholarly journals Drug Repurposing for Triple-Negative Breast Cancer

2020 ◽  
Vol 10 (4) ◽  
pp. 200
Author(s):  
Marta Ávalos-Moreno ◽  
Araceli López-Tejada ◽  
Jose L. Blaya-Cánovas ◽  
Francisca E. Cara-Lupiañez ◽  
Adrián González-González ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Biological Networks ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
High Rate ◽  
Investigational Drug ◽  
Oxide Synthase

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer which presents a high rate of relapse, metastasis, and mortality. Nowadays, the absence of approved specific targeted therapies to eradicate TNBC remains one of the main challenges in clinical practice. Drug discovery is a long and costly process that can be dramatically improved by drug repurposing, which identifies new uses for existing drugs, both approved and investigational. Drug repositioning benefits from improvements in computational methods related to chemoinformatics, genomics, and systems biology. To the best of our knowledge, we propose a novel and inclusive classification of those approaches whereby drug repurposing can be achieved in silico: structure-based, transcriptional signatures-based, biological networks-based, and data-mining-based drug repositioning. This review specially emphasizes the most relevant research, both at preclinical and clinical settings, aimed at repurposing pre-existing drugs to treat TNBC on the basis of molecular mechanisms and signaling pathways such as androgen receptor, adrenergic receptor, STAT3, nitric oxide synthase, or AXL. Finally, because of the ability and relevance of cancer stem cells (CSCs) to drive tumor aggressiveness and poor clinical outcome, we also focus on those molecules repurposed to specifically target this cell population to tackle recurrence and metastases associated with the progression of TNBC.

scholarly journals A novel humanized Frizzled-7-targeting antibody enhances antitumor effects of Bevacizumab against triple-negative breast cancer via blocking Wnt/β-catenin signaling pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Wei Xie ◽  
Huijie Zhao ◽  
Fengxian Wang ◽  
Yiyun Wang ◽  
Yuan He ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Near Infrared ◽  
Triple Negative ◽  
Vasculogenic Mimicry ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Antitumor Effects ◽  
Mouse Xenograft Model

Abstract Background Anti-angiogenic therapy has been widely applied to the clinical treatment of malignant tumors. However, the efficacy of such treatments has been called into question, especially in triple-negative breast cancer (TNBC). Bevacizumab, the first anti-angiogenic agent approved by FDA, actually increases invasive and metastatic properties of TNBC cells, resulting from the activation of Wnt/β-catenin signaling in response to hypoxia. As a critical receptor of Wnt/β-catenin signaling, Frizzled-7 (Fzd7) is aberrantly expressed in TNBC, indicating Fzd7 a potential target for developing drugs to be combined with anti-angiogenic agents. Methods Hybridoma technique and antibody humanization technique were utilized to generate a Fzd7-targeting antibody (SHH002-hu1). Biolayer interferometry (BLI) assay and near infrared (NIR) imaging were conducted to detect the affinity and targeting ability of SHH002-hu1. Next, whether SHH002-hu1 could suppress the invasion and migration of TNBC cells induced by Bevacizumab were validated, and the underlying molecular mechanisms were elucidated by luciferase reporter and western blot assays. The nude-mice transplanted TNBC models were established to assess the anti-TNBC activities of SHH002-hu1 when combined with Bevacizumab. Then, the effects on putative TNBC stem-like cells and Wnt/β-catenin signaling were evaluated by immunofluorescence (IF). Further, the tumor-initiating and self-renew capacity of TNBC cells were studied by secondary nude mouse xenograft model and sphere formation assay. In addition, the effects of SHH002-hu1 on the adaptation of TNBC cells to hypoxia were evaluated by the detection of vasculogenic mimicry (VM) and hypoxia-inducible factor-1α (HIF-1α) transcriptional activity. Results The novel humanized antibody targeting Fzd7 (SHH002-hu1) exhibited extremely high affinity with Fzd7, and specifically targeted to Fzd7+ cells and tumor tissues. SHH002-hu1 repressed invasion, migration and epithelial-mesenchymal cell transformation (EMT) of TNBC cells induced by Bevacizumab through abating Wnt/β-catenin signaling. SHH002-hu1 significantly enhanced the capacity of Bevacizumab to inhibit the growth of TNBC via reducing the subpopulation of putative TNBC stem-like cells, further attenuating Bevacizumab-enhanced tumor-initiating and self-renew capacity of TNBC cells. Moreover, SHH002-hu1 effectively restrained the adaptation of TNBC cells to hypoxia via disrupting Wnt/β-catenin signaling. Conclusion SHH002-hu1 significantly enhances the anti-TNBC capacity of Bevacizumab, and shows the potential of preventing TNBC recurrence, suggesting SHH002-hu1 a good candidate for the synergistic therapy together with Bevacizumab.

Expression of Transgelin in Triple Negative and Non Triple Negative Breast Cancer: A Differential Study

2020 ◽  
Vol 106 (1_suppl) ◽  
pp. 20-20
Author(s):  
NS Tolba ◽  
AS Alsedfy ◽  
SW Skandar ◽  
YM El-Kerm
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
High Rate ◽  
Targeted Treatment ◽  
Her2 Status ◽  
Altered Expression ◽  
Wide Range ◽  
Significant Difference

Introduction: Triple negative breast cancer (TNBC) is defined by the absence of ER expression, PR expression and HER2 amplification. No targeted treatment is available for TNBC and chemotherapy remains the best therapeutic option. However, in the case of recurrence or chemo-resistance, therapeutic options are very limited. TNBC presents a high rate of proliferation and is highly aggressive having low survival rate. As the complexity of this disease is being simplified over time, new targets are also being discovered for the treatment of this disease. Therefore, there is still need for new biomarkers, which would serve for targeted treatment. Transgelin was proposed as a new potential cancer biomarker. Altered expression of Transgelin has been described in a wide range of cancers, often with contradictory results. The aim of the study was to compare Transgelin expression across molecular subtypes of breast cancer, to identify if it can be used as a future molecular targeted protein for TNBC. Material and Methods: Transgelin immunohistochemistry was applied on 60 retrospectively collected paraffin blocks of patients presenting with invasive breast carcinoma (NST) having different molecular subtypes. Blocks were collected between 2015 and 2016 from Pathology department, Medical Research Institute, Egypt. Her2 equivocal cases were excluded from the study. Results: Transgelin expression was positive in 23 cases and negative in 37 cases. There was a statistically significant difference between (Transgelin +) and (Transgelin -) cases being highly expressed in TNBC in comparison to other molecular subtypes. It was also highly expressed in tumors with large size, high grade, positive lymph-vascular invasion status & lymph node metastasis. There was no statistically significant difference between (Transgelin+) and (Transgelin-) as regards age and Her2 status. Conclusions: Transgelin is an aggressive biomarker differentially expressed among the molecular breast cancer subtypes with high expression in TNBC. Transgelin may provide a potential target for future treatment of TNBC.

scholarly journals A Polyphenol Rich Muscadine Grape Extract Reduces Triple Negative Breast Cancer Cell Migration in Association with Changes in Cell Morphology and Motility-Related Proteins

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 325-325
Author(s):  
Patricia Gallagher ◽  
Marianne Collard ◽  
Heather Brown-Harding ◽  
Elisabeth Tallant
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Confocal Microscopy ◽  
Triple Negative Breast Cancer ◽  
Cell Shape ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Dependent Manner ◽  
Grape Extract ◽  
Muscadine Grape

Abstract Objectives Triple negative breast cancer (TNBC) is a subtype of breast cancer characterized by the lack of estrogen receptors, progesterone receptors and over-expression of the human epidermal growth factor receptor 2, limiting targeted treatment.  TNBC disproportionally affects ethnic minorities and younger women and has a high propensity to metastasize, often within 5 years of diagnosis, making it one of the most aggressive breast cancer subtypes.  We showed that treatment with a proprietary muscadine grape extract (MGE) reduced the growth and metastasis of TNBC in mice.  Muscadine grapes (V. Rotundifolia) are rich in polyphenols and extracts produced from muscadine grape seed and skin are marketed as nutraceuticals for their anti-oxidant, anti-inflammatory, and anti-cancer properties.  The goal of these studies was to determine the molecular mechanisms for the reduction in metastatic growth by MGE. Methods A proprietary extract was prepared from muscadine grape seeds and skins.  Migration of MDA-MB-231 and BT-549 cells was measured by a scratch wound assay, cell shape was visualized by confocal microscopy and mRNA/proteins that participate in cell migration/motility were measured by RT-PCR and western blot hybridization. Results The extract reduced the migration of MDA-MB-231 and BT-549 TNBC cells in a dose-dependent manner.  The reduction in cell migration was associated with MGE-induced alterations in cell shape and actin filament organization, visualized by confocal microscopy.  The extract caused an apparent loss of cell polarization in MDA-MB-231 cells and a reduction in the presence of filopodia in BT-549 cells.  The MGE-induced reduction in migration and alterations in cell shape and polarization were associated with a decrease in Rho kinase ROCK1/2 mRNA and protein as well as both the mRNA and protein expression of RHAMM, a protein that is implicated in both cell motility and breast cancer progression. Conclusions These results demonstrate that a proprietary MGE reduces TNBC cell migration, in association with changes in cell shape and cytoskeleton as well as proteins that regulate migration and motility, suggesting that treatment of TNBC patients with MGE may slow or prevent metastatic progression. Funding Sources Chronic Disease Research Fund.

scholarly journals IGF-1/IGF-1R/FAK/YAP Transduction Signaling Prompts Growth Effects in Triple-Negative Breast Cancer (TNBC) Cells

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1010 ◽  
Author(s):  
Damiano Cosimo Rigiracciolo ◽  
Nijiro Nohata ◽  
Rosamaria Lappano ◽  
Francesca Cirillo ◽  
Marianna Talia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Triple Negative ◽  
Cancer Genomics ◽  
Treatment Options ◽  
Signal Transduction Pathway ◽  
Growth Potential ◽  
Nuclear Accumulation

Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype that currently lacks targeted treatment options. The role played by the insulin-like growth factor-1 (IGF-1) and its cognate receptor IGF-1R in TNBC has been reported. Nevertheless, the molecular mechanisms by which the IGF-1/IGF-1R system may contribute to TNBC progression still remains to be fully understood. By computational analysis of the vast cancer genomics information in public databases (TCGA and METABRIC), we obtained evidence that high IGF-1 or IGF-1R levels correlate with a worse clinical outcome in TNBC patients. Further bioinformatics analysis revealed that both the focal adhesion and the Hippo pathways are enriched in TNBC harboring an elevated expression of IGF-1 or IGF-1R. Mechanistically, we found that in TNBC cells, the IGF-1/IGF-1R system promotes the activation of the FAK signal transduction pathway, which in turn regulates the nuclear accumulation of YAP (yes-associated protein/yes-related protein) and the expression of its target genes. At the biological level, we found that the IGF-1/IGF-1R-FAK-YAP network cascade triggers the growth potential of TNBC cells, as evaluated in different experimental systems. Overall, our results suggest that the IGF-1/IGF-1R/FAK/YAP axis may contribute to the progression of the aggressive TNBC subtype.

scholarly journals Sanguisorba officinalis L. Suppresses Triple-Negative Breast Cancer Metastasis by Inhibiting Late-Phase Autophagy via Hif-1α/Caveolin-1 Signaling

2020 ◽  
Vol 11 ◽  
Author(s):  
Neng Wang ◽  
Gulizeba Muhetaer ◽  
Xiaotong Zhang ◽  
Bowen Yang ◽  
Caiwei Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Triple Negative ◽  
Late Phase ◽  
Breast Cancer Metastasis ◽  
Chinese Herbs ◽  
Caveolin 1 ◽  
Sanguisorba Officinalis

Sanguisorba officinalis L. (SA) is a common herb for cancer treatment in the clinic, particularly during the consolidation phase to prevent occurrence or metastasis. Nevertheless, there are limited studies reporting the molecular mechanisms about its anti-metastatic function. It is well demonstrated that autophagy is one of the critical mechanisms accounting for metastasis and anti-cancer pharmacological actions of Chinese herbs. On the threshold, the regulatory effects and molecular mechanisms of SA in suppressing autophagy-related breast cancer metastasis were investigated in this study. In vitro findings demonstrated that SA potently suppressed the proliferation, colony formations well as metastasis process in triple-negative breast cancer. Network and biological analyses predicted that SA mainly targeted caveolin-1 (Cav-1) to induce anti-metastatic effects, and one of the core mechanisms was via regulation of autophagy. Further experiments—including western blotting, transmission electron microscopy, GFP-mRFP-LC3 immunofluorescence, and lysosomal-activity detection—validated SA as a potent late-stage autophagic inhibitor by increasing microtubule-associated light chain 3-II (LC3-II) conversion, decreasing acidic vesicular-organelle formation, and inducing lysosomal dysfunction even under conditions of either starvation or hypoxia. Furthermore, the anti-autophagic and anti-metastatic activity of SA was Cav-1-dependent. Specifically, Cav-1 knockdown significantly facilitated SA-mediated inhibition of autophagy and metastasis. Furthermore, hypoxia inducible factor-1α (Hif-1α) overexpression attenuated the SA-induced inhibitory activities on Cav-1, autophagy, and metastasis, indicating that SA may have inhibited autophagy-related metastasis via Hif-1α/Cav-1 signaling. In both mouse breast cancer xenograft and zebrafish xenotransplantation models, SA inhibited breast cancer growth and inhibited late-phase autophagy in vivo, which was accompanied by suppression of Hif-1α/Cav-1 signaling and the epithelial-mesenchymal transition. Overall, our findings not only indicate that SA acts as a novel late-phase autophagic inhibitor with anti-metastatic activities in triple-negative breast cancer, but also highlight Cav-1 as a regulator in controlling late-phase autophagic activity.

scholarly journals ITGA2is a target of miR-206 promoting cancer stemness and lung metastasis through enhancedACLYandCCND1expression in triple negative breast cancer

2019 ◽  
Author(s):  
Valery Adorno-Cruz ◽  
Andrew D. Hoffmann ◽  
Xia Liu ◽  
Brian Wray ◽  
Ruth A. Keri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Lipid Metabolism ◽  
Lung Metastasis ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Fatty Acid Biosynthesis ◽  
Migration And Invasion ◽  
Cancer Stemness

AbstractAccumulating evidence demonstrates that cancer stemness is essential for both tumor development and progression, regulated by multi-layer factors at genetic, epigenetic and micro-environmental levels. However, how to target stemness-driven plasticity and eliminate metastasis remains one of the biggest challenges in the clinic. We aim to identify novel molecular mechanisms underlying stemness of triple negative breast cancer (TNBC) which frequently metastasizes to the visceral organs but lacks targeted therapies. Following our previous discovery of miR-206 as an epigenetic suppressor of tumorigenesis and metastasis, we now report that the integrin receptor CD49b-encodingITGA2is an oncogenic target of miR-206 in TNBC.ITGA2knockdown abolished cancer stemness (mammosphere formation, pluripotency marker expression, and FAK phosphorylation), inhibited cell cycling, compromised migration and invasion, and thereby decreasing lung metastasis of TNBC. RNA sequencing analyses of breast cancer cells revealed thatITGA2knockdown inhibits gene expression essential for both classical integrin-regulated pathways (cell cycle, wounding response, protein kinase, etc) and newly identified pathways such as lipid metabolism. Notably,ACLY-encoded ATP citrate lyase is one of the top targets in CD49b-regulated lipid metabolism andCCND1-encoded Cyclin D1 represents regulation of cell cycle and many other pathways. ACLY, known to catalyze the formation of cytosolic acetyl-CoA for fatty acid biosynthesis, is indispensable for cancer stemness. Overexpression ofCCND1rescues the phenotype ofITGA2knockdown-induced cell cycle arrest. High expression levels of theITGA2/ACLY/CCND1axis are correlated with an unfavorable relapse-free survival of patients with high grade breast cancer, in both basal-like and other subtypes. This study identifiesITGA2as a potential therapeutic target of TNBC stemness and metastasis.

scholarly journals SphK2/S1P promotes metastasis in triple negative breast cancer through PAK1/LIMK1/Cofilin1 signaling pathway

2020 ◽  
Author(s):  
Weiwei Shi ◽  
Ding Ma ◽  
Yin Cao ◽  
Lili Hu ◽  
Shuwen Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Signaling Pathway ◽  
Lung Metastasis ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Specific Inhibitor ◽  
Downstream Signaling

Abstract Background: Triple negative breast cancer (TNBC) features poor prognosis which partialy attributed to the high metastasis rate. However, there is no effective target for systemic TNBC therapy due to the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors (ER, PR, HER-2) up to date. In the present study, we evaluated the role of sphingosine kinase 2 (SphK2) and its catalysate sphingosine-1-phosphate (S1P) in TNBC metastasis, and the antitumor activity of SphK2 specific inhibitor ABC294640 in TNBC metastasis. Methods: The function of SphK2 and S1P in migration of TNBC cells was evaluated by Transwell migration and wound healing assays. The molecular mechanisms of SphK2/S1P mediating TNBC metastasis were investigated using cell line establishment, western blot, histological examination and immunohistochemistry assays. The antitumor activity of ABC294640 was examined in TNBC lung metastasis model in vivo. Results: SphK2 regulated TNBC cells migration through the generation of S1P. Targeting SphK2 with ABC294640 inhibited TNBC lung metastasis in vivo . p21-activated kinase 1 (PAK1), p-Lin-11/Isl-1/Mec-3 kinase 1 (LIMK1) and Cofilin1 was the downstream signaling cascade of SphK2/S1P. Inhibition of PAK1 suppressed SphK2/S1P induced TNBC cells migration. Concusion: SphK2/S1P promotes TNBC metastasis through the activation of the PAK1/LIMK1/Cofilin1 signaling pathway. ABC294640 potently inhibits TNBC metastasis in vivo which could be developed as a novel agent for the clinical treatment of TNBC.

scholarly journals Overexpression of CCNE1 confers a poorer prognostic in triple negative breast cancer identified by bioinformatic analysis

2020 ◽  
Author(s):  
Qianqian Yuan ◽  
Lewei Zheng ◽  
Yiqin Liao ◽  
Gaosong Wu
Keyword(s):  
Breast Cancer ◽  
Survival Analysis ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Cancer Survival ◽  
Process Analysis ◽  
Interaction Network ◽  
Bioinformatic Analysis ◽  
Gene Expression Omnibus

Abstract Background. Triple-negative breast cancer (TNBC) is a major subtype of breast cancer. Due to the lack of effective therapeutic targets, the prognosis is poor. In order to find an effective target, despite many efforts, the molecular mechanisms of TNBC are still not well understood which remain to be a profound clinical challenge.Methods. To identify the candidate genes in the carcinogenesis and progression of TNBC, microarray datasets GSE36693 and GSE65216 were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and functional and pathway enrichment analyses were performed using the Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) databases via DAVID. We constructed the protein-protein interaction network (PPI) and the performed the module analysis using STRING and Cytoscape. Then we reanalyzed the selected DEGs genes and the survival analysis was performed using cBioportal.Results. A total of 140 DEGs were identified, consisting of 69 upregulated genes and 71 downregulated genes. Three hub genes were up-regulated among the selected genes from PPI and biological process analysis uncovered the fact that these genes were mainly enriched in p53 pathway and the pathways in cancer. Survival analysis showed that only CCNE1 may be involved in the carcinogenesis, invasion or recurrence of TNBC. Conclusion. CCNE1 could confer a poorer prognostic in TNBC identified by bioinformatic analysis and play key roles in the progression of TNBC which may contribute potential targets for the diagnosis, treatment and prognosis assessment of TNBC.

scholarly journals Disrupting the CmP signaling network unveils novel biomarkers for triple negative breast cancer in Caucasian American women

2021 ◽  
Author(s):  
Johnathan Abou-Fadel ◽  
Muaz Bhalli ◽  
Brian Grajeda ◽  
Jun Zhang
Keyword(s):  
Breast Cancer ◽  
Racial Differences ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Signaling Network ◽  
Caucasian American ◽  
American Women ◽  
Signaling Complex ◽  
Novel Biomarkers

Objective: Triple-negative breast cancer (TNBC) constitutes ~15 percent of all diagnosed invasive breast cancer cases with limited options for treatment since immunotherapies that target the ER, PR and HER2 receptors are ineffective. Progesterone (PRG) is capable of inducing its effects through either classic, non-classic, or combined responses by binding to classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs). Under PRG-induced actions, we previously demonstrated that the CSC (CCM signaling complex) can couple both nPRs and mPRs into a CmPn signaling network which plays an important role in nPR(+) breast cancer tumorigeneses. We recently defined the novel CmP signaling network in TNBC cells, which overlapped with our previously defined CmPn network in nPR(+) breast cancer cells. Materials and Methods: Under mPRs-specific steroid actions, we measured alterations to key tumorigenesis pathways in Caucasian American Women (CAW)-TNBC cells, with RNAseq and Proteomic approaches. Results: TNBC in CAW share similar altered signaling pathways, under mPRs-specific steroid actions, demonstrating the overall aggressive nature of TNBCs, regardless of racial differences. Furthermore, in this report, we have identified 21 new CAW-TNBC specific candidate biomarkers that reinforce the definitive role of the CmP signaling network in TNBC tumorigenesis, initially identified in our previous studies with AAW-TNBCs. This new set of potential prognostic biomarkers may revolutionize molecular mechanisms and currently known concepts of tumorigenesis in CAW-TNBCs, leading to hopeful new therapeutic strategies.

scholarly journals Drug Repositioning and Subgroup Discovery for Precision Medicine Implementation in Triple Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6278
Author(s):  
Zainab Al-Taie ◽  
Mark Hannink ◽  
Jonathan Mitchem ◽  
Christos Papageorgiou ◽  
Chi-Ren Shyu
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Drug Repositioning ◽  
Subgroup Discovery ◽  
Patients With Cancer ◽  
Wet Lab ◽  
The Common ◽  
Genetic Profiles ◽  
Substantial Heterogeneity

Breast cancer (BC) is the leading cause of death among female patients with cancer. Patients with triple-negative breast cancer (TNBC) have the lowest survival rate. TNBC has substantial heterogeneity within the BC population. This study utilized our novel patient stratification and drug repositioning method to find subgroups of BC patients that share common genetic profiles and that may respond similarly to the recommended drugs. After further examination of the discovered patient subgroups, we identified five homogeneous druggable TNBC subgroups. A drug repositioning algorithm was then applied to find the drugs with a high potential for each subgroup. Most of the top drugs for these subgroups were chemotherapy used for various types of cancer, including BC. After analyzing the biological mechanisms targeted by these drugs, ferroptosis was the common cell death mechanism induced by the top drugs in the subgroups with neoplasm subdivision and race as clinical variables. In contrast, the antioxidative effect on cancer cells was the common targeted mechanism in the subgroup of patients with an age less than 50. Literature reviews were used to validate our findings, which could provide invaluable insights to streamline the drug repositioning process and could be further studied in a wet lab setting and in clinical trials.

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