Therapeutic Potential of Thymoquinone in Triple-Negative Breast Cancer Prevention and Progression through the Modulation of the Tumor Microenvironment

To date, the tumor microenvironment (TME) has gained considerable attention in various areas of cancer research due to its role in driving a loss of immune surveillance and enabling rapid advanced tumor development and progression. The TME plays an integral role in driving advanced aggressive breast cancers, including triple-negative breast cancer (TNBC), a pivotal mediator for tumor cells to communicate with the surrounding cells via lymphatic and circulatory systems. Furthermore, the TME plays a significant role in all steps and stages of carcinogenesis by promoting and stimulating uncontrolled cell proliferation and protecting tumor cells from the immune system. Various cellular components of the TME work together to drive cancer processes, some of which include tumor-associated adipocytes, fibroblasts, macrophages, and neutrophils which sustain perpetual amplification and release of pro-inflammatory molecules such as cytokines. Thymoquinone (TQ), a natural chemical component from black cumin seed, is widely used traditionally and now in clinical trials for the treatment/prevention of multiple types of cancer, showing a potential to mitigate components of TME at various stages by various pathways. In this review, we focus on the role of TME in TNBC cancer progression and the effect of TQ on the TME, emphasizing their anticipated role in the prevention and treatment of TNBC. It was concluded from this review that the multiple components of the TME serve as a critical part of TNBC tumor promotion and stimulation of uncontrolled cell proliferation. Meanwhile, TQ could be a crucial compound in the prevention and progression of TNBC therapy through the modulation of the TME.

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The MicroRNA miR-210 Is Expressed by Cancer Cells but Also by the Tumor Microenvironment in Triple-Negative Breast Cancer

Journal of Histochemistry & Cytochemistry ◽

10.1369/0022155417702849 ◽

2017 ◽

Vol 65 (6) ◽

pp. 335-346 ◽

Cited By ~ 10

Author(s):

Isabelle Bar ◽

Ahmad Merhi ◽

Fadi Abdel-Sater ◽

Abduelhakem Ben Addi ◽

Sara Sollennita ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

New Class ◽

Cellular Context ◽

Tnbc Subtype

The triple-negative breast cancer (TNBC) subtype occurs in about 15% of breast cancer and is an aggressive subtype of breast cancer with poor outcome. Furthermore, treatment of patients with TNBC is more challenging due to the heterogeneity of the disease and the absence of well-defined molecular targets. Microribonucleic acid (RNA) represents a new class of biomarkers that are frequently dysregulated in cancer. It has been described that the microRNA miR-210 is highly expressed in TNBC, and its overexpression had been linked to poor prognosis. TNBC are often infiltrated by immune cells that play a key role in cancer progression. The techniques traditionally used to analyze miR-210 expression such as next generation sequencing or quantitative real-time polymerase chain reaction (PCR) do not allow the precise identification of the cellular subtype expressing the microRNA. In this study, we have analyzed miR-210 expression by in situ hybridization in TNBC. The miR-210 signal was detected in tumor cells, but also in the tumor microenvironment, in a region positive for the pan-leucocyte marker CD45-LCA. Taken together, our results demonstrate that miR-210 is expressed in tumor cells but also in the tumor microenvironment. Our results also highlight the utility of using complementary approaches to take into account the cellular context of microRNA expression.

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The Anticancer Effects of Flavonoids through miRNAs Modulations in Triple-Negative Breast Cancer

Nutrients ◽

10.3390/nu13041212 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1212

Author(s):

Getinet M. Adinew ◽

Equar Taka ◽

Patricia Mendonca ◽

Samia S. Messeha ◽

Karam F. A. Soliman

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Therapeutic Potential ◽

Biological Activities ◽

Therapeutic Option ◽

Mesenchymal Transition ◽

Anticancer Effects

Triple- negative breast cancer (TNBC) incidence rate has regularly risen over the last decades and is expected to increase in the future. Finding novel treatment options with minimum or no toxicity is of great importance in treating or preventing TNBC. Flavonoids are new attractive molecules that might fulfill this promising therapeutic option. Flavonoids have shown many biological activities, including antioxidant, anti-inflammatory, and anticancer effects. In addition to their anticancer effects by arresting the cell cycle, inducing apoptosis, and suppressing cancer cell proliferation, flavonoids can modulate non-coding microRNAs (miRNAs) function. Several preclinical and epidemiological studies indicate the possible therapeutic potential of these compounds. Flavonoids display a unique ability to change miRNAs’ levels via different mechanisms, either by suppressing oncogenic miRNAs or activating oncosuppressor miRNAs or affecting transcriptional, epigenetic miRNA processing in TNBC. Flavonoids are not only involved in the regulation of miRNA-mediated cancer initiation, growth, proliferation, differentiation, invasion, metastasis, and epithelial-to-mesenchymal transition (EMT), but also control miRNAs-mediated biological processes that significantly impact TNBC, such as cell cycle, immune system, mitochondrial dysregulation, modulating signaling pathways, inflammation, and angiogenesis. In this review, we highlighted the role of miRNAs in TNBC cancer progression and the effect of flavonoids on miRNA regulation, emphasizing their anticipated role in the prevention and treatment of TNBC.

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KDM4C Activity Modulates Cell Proliferation and Chromosome Segregation in Triple-Negative Breast Cancer

Breast Cancer Basic and Clinical Research ◽

10.4137/bcbcr.s40182 ◽

2016 ◽

Vol 10 ◽

pp. BCBCR.S40182 ◽

Cited By ~ 2

Author(s):

Jeison Garcia ◽

Fernando Lizcano

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Chromosome Segregation ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Human Cancer ◽

Histone Demethylase ◽

Breast Cancer Cell Lines ◽

Demethylase Activity

The Jumonji-containing domain protein, KDM4C, is a histone demethylase associated with the development of several forms of human cancer. However, its specific function in the viability of tumoral lineages is yet to be determined. This work investigates the importance of KDM4C activity in cell proliferation and chromosome segregation of three triple-negative breast cancer cell lines using a specific demethylase inhibitor. Immunofluorescence assays show that KDM4C is recruited to mitotic chromosomes and that the modulation of its activity increases the number of mitotic segregation errors. However, 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) cell proliferation assays demonstrate that the demethylase activity is required for cell viability. These results suggest that the histone demethylase activity of KDM4C is essential for breast cancer progression given its role in the maintenance of chromosomal stability and cell growth, thus highlighting it as a potential therapeutic target.

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Lamin B2 promotes the progression of triple negative breast cancer via mediating cell proliferation and apoptosis

Bioscience Reports ◽

10.1042/bsr20203874 ◽

2021 ◽

Vol 41 (1) ◽

Author(s):

Cui-Cui Zhao ◽

Jing Chen ◽

Li-Ying Zhang ◽

Hong Liu ◽

Chuan-Gui Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

The Cancer Genome Atlas ◽

Proliferation And Apoptosis

Abstract Triple negative breast cancer (TNBC) is a more common type of breast cancer with high distant metastasis and poor prognosis. The potential role of lamins in cancer progression has been widely revealed. However, the function of lamin B2 (LMNB2) in TNBC progression is still unclear. The present study aimed to investigate the role of LMNB2 in TNBC. The cancer genome atlas (TCGA) database analysis and immunohistochemistry (IHC) were performed to examine LMNB2 expression levels. LMNB2 short hairpin RNA plasmid or lentivirus was used to deplete the expression of LMNB2 in human TNBC cell lines including MDA-MB-468 and MDA-MB-231. Alterations in cell proliferation and apoptosis in vitro and the nude mouse tumorigenicity assay in vivo were subsequently analyzed. The human TNBC tissues shown high expression of LMNB2 according to the bioinformation analysis and IHC assays. LMNB2 expression was correlated with the clinical pathological features of TNBC patients, including pTNM stage and lymph node metastasis. Through in vitro and in vivo assays, we confirmed LMNB2 depletion suppressed the proliferation and induced the apoptosis of TNBC cells, and inhibited tumor growth of TNBC cells in mice, with the decrease in Ki67 expression or the increase in caspase-3 expression. In conclusion, LMNB2 may promote TNBC progression and could serve as a potential therapeutic target for TNBC treatment.

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Dezocine, An Opioid Analgesic, Exerts Antitumor Effects in Triple-Negative Breast Cancer by Targeting Nicotinamide Phosphoribosyltransferase

Frontiers in Pharmacology ◽

10.3389/fphar.2021.600296 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chenyang Xue ◽

Wei Chen ◽

Aiwu Yuan ◽

Cheng Chen ◽

Shuaihu Li ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Opioid Analgesic ◽

Migration And Invasion ◽

Antitumor Effects ◽

Nicotinamide Phosphoribosyltransferase

Opioids are a potential adjuvant treatment for certain cancers; while they are primarily used to relieve chronic pain, these drugs may also affect cancer progression and recurrence. Dezocine is one opioid commonly used in China, but its effects on cancer cells are unknown. Here, we demonstrated the inhibitory effect of dezocine on triple-negative breast cancer (TNBC) cells, and determined the underlying molecular mechanism. We found that dezocine suppressed cell proliferation, migration and invasion, and induced apoptosis in TNBC cells. Xenograft models demonstrated the inhibitory effects of dezocine treatment on TNBC tumor growth in vivo. The anticancer effects of dezocine were independent of opioid receptors, which are not highly expressed by normal breast or breast cancer tissues. A pull-down assay and LC-MS/MS analysis indicated that dezocine directly targets NAMPT: computer modeling verified that the free energy of dezocine kinetically bound into the pocket of NAMPT was −17.4 kcal/mol. Consequently, dezocine treatment inhibited NAMPT enzyme activity, resulting in cellular NAD abolishment. We confirmed the dezocine-induced inhibition of cell proliferation by both NAMPT knockdown and upon treatment with the inhibitor FK866. Our results suggest that both dezocine and NAMPT might represent novel therapeutic targets for TNBC.

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Therapeutic Potential of a Novel αvβ3 Antagonist to Hamper the Aggressiveness of Mesenchymal Triple Negative Breast Cancer Sub-Type

Cancers ◽

10.3390/cancers11020139 ◽

2019 ◽

Vol 11 (2) ◽

pp. 139 ◽

Cited By ~ 11

Author(s):

Billy Hill ◽

Annachiara Sarnella ◽

Domenica Capasso ◽

Daniela Comegna ◽

Annarita Del Gatto ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Epithelial To Mesenchymal Transition ◽

Triple Negative ◽

Therapeutic Potential ◽

Migration And Invasion ◽

Αvβ3 Integrin ◽

Altered Expression ◽

Mesenchymal Transition

The mesenchymal sub-type of triple negative breast cancer (MES-TNBC) has a highly aggressive behavior and worse prognosis, due to its invasive and stem-like features, that correlate with metastatic dissemination and resistance to therapies. Furthermore, MES-TNBC is characterized by the expression of molecular markers related to the epithelial-to-mesenchymal transition (EMT) program and cancer stem cells (CSCs). The altered expression of αvβ3 integrin has been well established as a driver of cancer progression, stemness, and metastasis. Here, we showed that the high levels of αvβ3 are associated with MES-TNBC and therefore exploited the possibility to target this integrin to reduce the aggressiveness of this carcinoma. To this aim, MES-TNBC cells were treated with a novel peptide, named ψRGDechi, that we recently developed and characterized for its ability to selectively bind and inhibit αvβ3 integrin. Notably, ψRGDechi was able to hamper adhesion, migration, and invasion of MES-TNBC cells, as well as the capability of these cells to form vascular-like structures and mammospheres. In addition, this peptide reversed EMT program inhibits mesenchymal markers. These findings show that targeting αvβ3 integrin by ψRGDechi, it is possible to inhibit some of the malignant properties of MES-TNBC phenotype.

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Pentagalloyl glucose inhibits TNF‐α‐activated CXCL1/GRO-α expression and induces apoptosis‐related genes in triple-negative breast cancer cells

Scientific Reports ◽

10.1038/s41598-021-85090-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Patricia Mendonca ◽

Sumaih Alghamdi ◽

Samia Messeha ◽

Karam F. A. Soliman

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cell Lines ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Fold Increase ◽

Mapk Signaling ◽

Tnf Α ◽

Pentagalloyl Glucose

AbstractIn triple-negative breast cancer (TNBC), the tumor microenvironment is associated with increased proliferation, suppressing apoptotic mechanisms, an altered immune response, and drug resistance. The current investigation was designed to examine the natural compound pentagalloyl glucose (PGG) effects on TNF-α activated TNBC cell lines, MDA-MB-231 and MDA-MB-468. The results obtained showed that PGG reduced the expression of the cytokine GRO-α/CXCL1. PGG also inhibited IƙBKE and MAPK1 genes and the protein expression of IƙBKE and MAPK, indicating that GRO-α downregulation is possibly through NFƙB and MAPK signaling pathway. PGG also inhibited cell proliferation in both cell lines. Moreover, PGG induced apoptosis, modulating caspases, and TNF superfamily receptor genes. It also augmented mRNA of receptors DR4 and DR5 expression, which binds to TNF-related apoptosis-induced ligand, a potent and specific stimulator of apoptosis in tumors. Remarkably, PGG induced a 154-fold increase in TNF expression in MDA-MB-468 compared to a 14.6-fold increase in MDA-MB-231 cells. These findings indicate PGG anti-cancer ability in inhibiting tumor cell proliferation and GRO-α release and inducing apoptosis by increasing TNF and TNF family receptors' expression. Thus, PGG use may be recommended as an adjunct therapy for TNBC to increase chemotherapy effectiveness and prevent cancer progression.

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Dual therapeutic strategy targeting tumor cells and tumor microenvironment in triple-negative breast cancer

Journal of Cancer Research and Practice ◽

10.4103/jcrp.jcrp_13_20 ◽

2020 ◽

Vol 7 (4) ◽

pp. 139

Author(s):

Tsu-Yi Chao ◽

PamungkasBagus Satriyo ◽

Chi-Tai Yeh ◽

Jia-Hong Chen ◽

Teguh Aryandono ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Triple Negative Breast Cancer ◽

Therapeutic Strategy ◽

Triple Negative

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Targeting neurons in the tumor microenvironment with bupivacaine nanoparticles reduces breast cancer progression and metastases

10.1101/2021.05.18.444598 ◽

2021 ◽

Author(s):

Maya Kaduri ◽

Mor Sela ◽

Shaked Kagan ◽

Maria Poley ◽

Hanan Abumanhal-Masarweh ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Opioid Analgesic ◽

Neurite Growth

Neurons within the tumor microenvironment promote cancer progression, thus their local targeting has potential clinical benefits. We designed PEGylated lipid nanoparticles loaded with a non-opioid analgesic, bupivacaine, to target neurons within breast cancer tumors and suppress nerve-to-cancer crosstalk. In vitro, 100-nm nanoparticles were taken up readily by primary neurons, trafficking from the neuronal body and along the axons. We demonstrate that signaling between triple-negative breast cancer cells (4T1) and neurons involves secretion of cytokines stimulating neurite outgrowth. Reciprocally, neurons stimulated 4T1 proliferation, migration and survival through secretion of neurotransmitters. Bupivacaine curbs neurite growth and signaling with cancer cells, inhibiting cancer-cell viability. In vivo, bupivacaine-loaded nanoparticles administered intravenously, suppressed neurons in orthotopic triple-negative breast cancer tumors, inhibiting tumor growth and metastatic dissemination. Overall, our findings suggest that reducing nerve involvement in tumors is important for treating cancer.

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