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15 pages, 2059 KiB

Open AccessArticle

Crosstalk between Metabolite Production and Signaling Activity in Breast Cancer

by Cankut Çubuk, Carlos Loucera, María Peña-Chilet and Joaquin Dopazo

Int. J. Mol. Sci. 2023, 24(8), 7450; https://doi.org/10.3390/ijms24087450 - 18 Apr 2023

Cited by 2 | Viewed by 1190

The reprogramming of metabolism is a recognized cancer hallmark. It is well known that different signaling pathways regulate and orchestrate this reprogramming that contributes to cancer initiation and development. However, recent evidence is accumulating, suggesting that several metabolites could play a relevant role [...] Read more.

The reprogramming of metabolism is a recognized cancer hallmark. It is well known that different signaling pathways regulate and orchestrate this reprogramming that contributes to cancer initiation and development. However, recent evidence is accumulating, suggesting that several metabolites could play a relevant role in regulating signaling pathways. To assess the potential role of metabolites in the regulation of signaling pathways, both metabolic and signaling pathway activities of Breast invasive Carcinoma (BRCA) have been modeled using mechanistic models. Gaussian Processes, powerful machine learning methods, were used in combination with SHapley Additive exPlanations (SHAP), a recent methodology that conveys causality, to obtain potential causal relationships between the production of metabolites and the regulation of signaling pathways. A total of 317 metabolites were found to have a strong impact on signaling circuits. The results presented here point to the existence of a complex crosstalk between signaling and metabolic pathways more complex than previously was thought. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches)

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15 pages, 2772 KiB

Open AccessArticle

The Binomial “Inflammation-Epigenetics” in Breast Cancer Progression and Bone Metastasis: IL-1β Actions Are Influenced by TET Inhibitor in MCF-7 Cell Line

by Daniele Bellavia, Viviana Costa, Angela De Luca, Aurora Cordaro, Milena Fini, Gianluca Giavaresi, Fabio Caradonna and Lavinia Raimondi

Int. J. Mol. Sci. 2022, 23(23), 15422; https://doi.org/10.3390/ijms232315422 - 06 Dec 2022

Cited by 8 | Viewed by 1747

Abstract

The existence of a tight relationship between inflammation and epigenetics that in primary breast tumor cells can lead to tumor progression and the formation of bone metastases was investigated. It was highlighted how the induction of tumor progression and bone metastasis by Interleukin-1 [...] Read more.

The existence of a tight relationship between inflammation and epigenetics that in primary breast tumor cells can lead to tumor progression and the formation of bone metastases was investigated. It was highlighted how the induction of tumor progression and bone metastasis by Interleukin-1 beta, in a non-metastatic breast cancer cell line, MCF-7, was dependent on the de-methylating actions of ten-eleven translocation proteins (TETs). In fact, the inhibition of their activity by the Bobcat339 molecule, an inhibitor of TET enzymes, determined on the one hand, the modulation of the epithelial-mesenchymal transition process, and on the other hand, the reduction in the expression of markers of bone metastasis, indicating that the epigenetic action of TETs is a prerequisite for IL-1β-dependent tumor progression and bone metastasis formation. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches)

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20 pages, 7282 KiB

Open AccessArticle

The Effect of Aflatoxin B1 on Tumor-Related Genes and Phenotypic Characters of MCF7 and MCF10A Cells

by Mowaffaq Adam Ahmed Adam, Laina Zarisa Muhd Kamal, Mahibub Kanakal, Dinesh Babu, Saad Sabbar Dahham, Yasser Tabana, Bronwyn Lok, Brittany M. Bermoy, Muhammad Amir Yunus, Leslie Thian Lung Than, Khaled Barakat and Doblin Sandai

Int. J. Mol. Sci. 2022, 23(19), 11856; https://doi.org/10.3390/ijms231911856 - 06 Oct 2022

Cited by 1 | Viewed by 2592

Abstract

The fungal toxin aflatoxin B1 (AB1) and its reactive intermediate, aflatoxin B1-8, 9 epoxide, could cause liver cancer by inducing DNA adducts. AB1 exposure can induce changes in the expression of several cancer-related genes. In this study, the effect of AB1 exposure on [...] Read more.

The fungal toxin aflatoxin B1 (AB1) and its reactive intermediate, aflatoxin B1-8, 9 epoxide, could cause liver cancer by inducing DNA adducts. AB1 exposure can induce changes in the expression of several cancer-related genes. In this study, the effect of AB1 exposure on breast cancer MCF7 and normal breast MCF10A cell lines at the phenotypic and epigenetic levels was investigated to evaluate its potential in increasing the risk of breast cancer development. We hypothesized that, even at low concentrations, AB1 can cause changes in the expression of important genes involved in four pathways, i.e., p53, cancer, cell cycle, and apoptosis. The transcriptomic levels of BRCA1, BRCA2, p53, HER1, HER2, cMyc, BCL2, MCL1, CCND1, WNT3A, MAPK1, MAPK3, DAPK1, Casp8, and Casp9 were determined in MCF7 and MCF10A cells. Our results illustrate that treating both cells with AB1 induced cytotoxicity and apoptosis with reduction in cell viability in a concentration-dependent manner. Additionally, AB1 reduced reactive oxygen species levels. Phenotypically, AB1 caused cell-cycle arrest at G1, hypertrophy, and increased cell migration rates. There were changes in the expression levels of several tumor-related genes, which are known to contribute to activating cancer pathways. The effects of AB1 on the phenotype and epigenetics of both MCF7 and MCF10A cells associated with cancer development observed in this study suggest that AB1 is a potential risk factor for developing breast cancer. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches)

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15 pages, 3769 KiB

Open AccessArticle

Atropine Is a Suppressor of Epithelial–Mesenchymal Transition (EMT) That Reduces Stemness in Drug-Resistant Breast Cancer Cells

by Emad A. Ahmed, Mayyadah A. Alkuwayti and Hairul-Islam M. Ibrahim

Int. J. Mol. Sci. 2022, 23(17), 9849; https://doi.org/10.3390/ijms23179849 - 30 Aug 2022

Cited by 6 | Viewed by 1869

Abstract

Atropine (ATR) is extracted from a belladonna plant that belongs to a class of anticholinergic drugs and is therefore involved in the treatment of the overdose of cholinergic drugs or mushroom poisoning. It is a well-known blocker of muscarinic acetylcholine receptors (mAChRs) that [...] Read more.

Atropine (ATR) is extracted from a belladonna plant that belongs to a class of anticholinergic drugs and is therefore involved in the treatment of the overdose of cholinergic drugs or mushroom poisoning. It is a well-known blocker of muscarinic acetylcholine receptors (mAChRs) that are expressed in various tumor cells, including breast tumors from animal and human origin, but it has yet to be recommended as an anticancer drug. Our in silico docking analysis indicates that atropine has a roust virtual binding, with a stable binding energy, to two major signaling molecules involved in EMT regulation: E-cad and ZEB-2. For both, the gene and the protein expression level results show that atropine is an effective molecule in reducing epithelial–mesenchymal transition (EMT) and colony formation induced by TGF-B or carboplatin in both the mesenchymal-like cell line MDA-MB-231 and the epithelial-like cell line T47D. We conclude that atropine as a potential suppressor of EMT could be co-administrated with other chemotherapeutic drugs to reduce stemness in drug-resistant breast tumor cells. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches)

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13 pages, 5318 KiB

Open AccessArticle

Dimethyl Fumarate Induces Apoptosis via Inhibition of NF-κB and Enhances the Effect of Paclitaxel and Adriamycin in Human TNBC Cells

by Katsumasa Tsurushima, Masanobu Tsubaki, Tomoya Takeda, Takuya Matsuda, Akihiro Kimura, Honoka Takefuji, Akane Okada, Chiaki Sakamoto, Toshihiko Ishizaka and Shozo Nishida

Int. J. Mol. Sci. 2022, 23(15), 8681; https://doi.org/10.3390/ijms23158681 - 04 Aug 2022

Cited by 2 | Viewed by 1694

Abstract

Triple-negative breast cancer (TNBC) has the poorest prognosis of all breast cancer subtypes. Recently, the activation of NF-κB, which is involved in the growth and survival of malignant tumors, has been demonstrated in TNBC, suggesting that NF-κB may serve as a new therapeutic [...] Read more.

Triple-negative breast cancer (TNBC) has the poorest prognosis of all breast cancer subtypes. Recently, the activation of NF-κB, which is involved in the growth and survival of malignant tumors, has been demonstrated in TNBC, suggesting that NF-κB may serve as a new therapeutic target. In the present study, we examined whether dimethyl fumarate (DMF), an NF-κB inhibitor, induces apoptosis in TNBC cells and enhances the apoptosis-inducing effect of paclitaxel and adriamycin. Cell survival was analyzed by the trypan blue assay and apoptosis assay. Protein detection was examined by immunoblotting. The activation of NF-κB p65 was correlated with poor prognosis in patients with TNBC. DMF induced apoptosis in MDA-MB-231 and BT-549 cells at concentrations that were non-cytotoxic to the normal mammary cell line MCF-10A. Furthermore, DMF inhibited NF-κB nuclear translocation and Survivin, XIAP, Bcl-xL, and Bcl-2 expression in MDA-MB-231 and BT-549 cells. Moreover, DMF enhanced the apoptosis-inducing effect of paclitaxel and adriamycin in MDA-MB-231 cells. These findings suggest that DMF may be an effective therapeutic agent for the treatment of TNBC, in which NF-κB is constitutively active. DMF may also be useful as an adjuvant therapy to conventional anticancer drugs. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches)

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14 pages, 2625 KiB

Open AccessArticle

Targeting Tumor Acidosis and Regulatory T Cells Unmasks Anti-Metastatic Potential of Local Tumor Ablation in Triple-Negative Breast Cancer

by Corrine A. Nief, Alana Gonzales, Erika Chelales, Júlia Sroda Agudogo, Brian T. Crouch, Smita K. Nair and Nirmala Ramanujam

Int. J. Mol. Sci. 2022, 23(15), 8479; https://doi.org/10.3390/ijms23158479 - 30 Jul 2022

Cited by 5 | Viewed by 2582

Abstract

Triple-negative breast cancer (TNBC) is an immunologically heterogenous disease that lacks clinically actionable targets and is more likely to progress to metastatic disease than other types of breast cancer. Tumor ablation has been used to increase response rates to checkpoint inhibitors, which remain [...] Read more.

Triple-negative breast cancer (TNBC) is an immunologically heterogenous disease that lacks clinically actionable targets and is more likely to progress to metastatic disease than other types of breast cancer. Tumor ablation has been used to increase response rates to checkpoint inhibitors, which remain low for TNBC patients. We hypothesized that tumor ablation could produce an anti-tumor response without using checkpoint inhibitors if immunosuppression (i.e., Tregs, tumor acidosis) was subdued. Tumors were primed with sodium bicarbonate (200 mM p.o.) to reduce tumor acidosis and low-dose cyclophosphamide (100–200 mg/kg i.p.) to deplete regulatory T cells, as has been shown independently in previous studies. A novel injectable ablative was then used to necrose the tumor, release tumor antigens, and initiate an immune event that could create an abscopal effect. This combination of bicarbonate, cyclophosphamide, and ablation, called “BiCyclA”, was tested in three syngeneic models of TNBC: E0771 (C57BL/6), 67NR (BALB/c), and 4T1-Luc (BALB/c). In E0771 and 67NR, BiCyclA therapy significantly reduced tumor growth and cured 5/7 and 6/10 mice 50 days after treatment respectively. In the metastatic 4T1-Luc tumors, for which surgery and checkpoint inhibitors fail, BiCyclA cured 5/10 mice of primary tumors and lung metastases. Notably, CD4+ and CD8+ T cells were found to be crucial for the anti-metastatic response, and cured mice were able to resist tumor rechallenge, suggesting production of immune memory. Reduction of tumor acidity and regulatory T cells with ablation is a simple yet effective therapy for local and systemic tumor control with broad applicability as it is not limited by expensive supplies. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches)

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Review

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13 pages, 1473 KiB

Open AccessReview

Post-Translational Modification of ZEB Family Members in Cancer Progression

by Mi Kyung Park, Ho Lee and Chang Hoon Lee

Int. J. Mol. Sci. 2022, 23(23), 15127; https://doi.org/10.3390/ijms232315127 - 01 Dec 2022

Cited by 9 | Viewed by 1854

Abstract

Post-translational modification (PTM), the essential regulatory mechanisms of proteins, play essential roles in physiological and pathological processes. In addition, PTM functions in tumour development and progression. Zinc finger E-box binding homeobox (ZEB) family homeodomain transcription factors, such as ZEB1 and ZEB2, play a [...] Read more.

Post-translational modification (PTM), the essential regulatory mechanisms of proteins, play essential roles in physiological and pathological processes. In addition, PTM functions in tumour development and progression. Zinc finger E-box binding homeobox (ZEB) family homeodomain transcription factors, such as ZEB1 and ZEB2, play a pivotal role in tumour progression and metastasis by induction epithelial-mesenchymal transition (EMT), with activation of stem cell traits, immune evasion and epigenetic reprogramming. However, the relationship between ZEB family members’ post-translational modification (PTM) and tumourigenesis remains largely unknown. Therefore, we focussed on the PTM of ZEBs and potential therapeutic approaches in cancer progression. This review provides an overview of the diverse functions of ZEBs in cancer and the mechanisms and therapeutic implications that target ZEB family members’ PTMs. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches)

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27 pages, 2828 KiB

Open AccessReview

Dormancy in Breast Cancer, the Role of Autophagy, lncRNAs, miRNAs and Exosomes

by Leila Jahangiri and Tala Ishola

Int. J. Mol. Sci. 2022, 23(9), 5271; https://doi.org/10.3390/ijms23095271 - 09 May 2022

Cited by 12 | Viewed by 4196

Abstract

Breast cancer (BC) is the most frequently diagnosed cancer in women for which numerous diagnostic and therapeutic options have been developed. Namely, the targeted treatment of BC, for the most part, relies on the expression of growth factors and hormone receptors by these [...] Read more.

Breast cancer (BC) is the most frequently diagnosed cancer in women for which numerous diagnostic and therapeutic options have been developed. Namely, the targeted treatment of BC, for the most part, relies on the expression of growth factors and hormone receptors by these cancer cells. Despite this, close to 30% of BC patients may experience relapse due to the presence of minimal residual disease (MRD) consisting of surviving disseminated tumour cells (DTCs) from the primary tumour which can colonise a secondary site. This can lead to either detectable metastasis or DTCs entering a dormant state for a prolonged period where they are undetectable. In the latter, cells can re-emerge from their dormant state due to intrinsic and microenvironmental cues leading to relapse and metastatic outgrowth. Pre- and clinical studies propose that targeting dormant DTCs may inhibit metastasis, but the choice between keeping them dormant or forcing their “awakening” is still controversial. This review will focus on cancer cells’ microenvironmental cues and metabolic and molecular properties, which lead to dormancy, relapse, and metastatic latency in BC. Furthermore, we will focus on the role of autophagy, long non-coding RNAs (lncRNAs), miRNAs, and exosomes in influencing the induction of dormancy and awakening of dormant BC cells. In addition, we have analysed BC treatment from a viewpoint of autophagy, lncRNAs, miRNAs, and exosomes. We propose the targeted modulation of these processes and molecules as modern aspects of precision medicine for BC treatment, improving both novel and traditional BC treatment options. Understanding these pathways and processes may ultimately improve BC patient prognosis, patient survival, and treatment response. Full article

(This article belongs to the Special Issue Breast Cancer, Metastatic Breast Cancer, Therapeutic Approaches)

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