The Anticancer Properties of Silibinin: Its Molecular Mechanism and Therapeutic Effect in Breast Cancer

Background: Silibinin (SB), the main component of Silymarin (SM), is a natural substance obtained from the seeds of the milk thistle. SM contains up to 70% of SB as two isoforms: A and B. It has an antioxidant and anti-inflammatory effect on hepatocytes and is known to inhibit cell proliferation, induce apoptosis, and curb angiogenesis. SB has demonstrated activity against many cancers, such as skin, liver, lung, bladder, and breast carcinomas. Methods: his review presents current knowledge of the use of SM in breast cancer, this being one of the most common types of cancer in women. It describes selected molecular mechanisms of the action of SM; for example, although SB influences both Estrogen Receptors (ER), α and β, it has opposite effects on the two. Its action on ERα influences the PI3K/AKT/mTOR and RAS/ERK signaling pathways, while by up-regulating ERβ, it increases the numbers of apoptotic cells. In addition, ERα is involved in SB-induced autophagy, while ERβ is not. Interestingly, SB also inhibits metastasis by suppressing TGF-β2 expression, thus suppressing Epithelial to Mesenchymal Transition (EMT). It also influences migration and invasive potential via the Jak2/STAT3 pathway. Results: SB may be a promising enhancement of BC treatment: when combined with chemotherapeutic drugs such as carboplatin, cisplatin, and doxorubicin, the combination exerts a synergistic effect against cancer cells. This may be of value when treating aggressive types of mammary carcinoma. Conclusion: Summarizing, SB inhibits proliferation, induces apoptosis, and restrains metastasis via several mechanisms. It is possible to combine SB with different anticancer drugs, an approach that represents a promising therapeutic strategy for patients suffering from BC.

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Consequences of EMT-Driven Changes in the Immune Microenvironment of Breast Cancer and Therapeutic Response of Cancer Cells

Journal of Clinical Medicine ◽

10.3390/jcm8050642 ◽

2019 ◽

Vol 8 (5) ◽

pp. 642 ◽

Cited By ~ 12

Author(s):

Snahlata Singh ◽

Rumela Chakrabarti

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Tumor Cells ◽

Epithelial To Mesenchymal Transition ◽

Therapeutic Response ◽

Current Knowledge ◽

Cell Contact ◽

Invasive Potential ◽

Mesenchymal Transition ◽

Tumor Growth And Metastasis

Epithelial-to-mesenchymal transition (EMT) is a process through which epithelial cells lose their epithelial characteristics and cell–cell contact, thus increasing their invasive potential. In addition to its well-known roles in embryonic development, wound healing, and regeneration, EMT plays an important role in tumor progression and metastatic invasion. In breast cancer, EMT both increases the migratory capacity and invasive potential of tumor cells, and initiates protumorigenic alterations in the tumor microenvironment (TME). In particular, recent evidence has linked increased expression of EMT markers such as TWIST1 and MMPs in breast tumors with increased immune infiltration in the TME. These immune cells then provide cues that promote immune evasion by tumor cells, which is associated with enhanced tumor progression and metastasis. In the current review, we will summarize the current knowledge of the role of EMT in the biology of different subtypes of breast cancer. We will further explore the correlation between genetic switches leading to EMT and EMT-induced alterations within the TME that drive tumor growth and metastasis, as well as their possible effect on therapeutic response in breast cancer.

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Two Faces of TGF-Beta1 in Breast Cancer

Mediators of Inflammation ◽

10.1155/2014/141747 ◽

2014 ◽

Vol 2014 ◽

pp. 1-16 ◽

Cited By ~ 97

Author(s):

Joanna Magdalena Zarzynska

Keyword(s):

Breast Cancer ◽

Cell Cycle Progression ◽

Epithelial To Mesenchymal Transition ◽

Current Knowledge ◽

Clinical Investigation ◽

Mesenchymal Transition ◽

Early Stages ◽

New Therapeutic Approaches ◽

Genes Encoding ◽

Life Threatening

Breast cancer (BC) is potentially life-threatening malignancy that still causes high mortality among women. Scientific research in this field is focused on deeper understanding of pathogenesis and progressing of BC, in order to develop relevant diagnosis and improve therapeutic treatment. Multifunctional cytokine TGF-β1 is one of many factors that have a direct influence on BC pathophysiology. Expression of TGF-β1, induction of canonical and noncanonical signaling pathways, and mutations in genes encoding TGF-β1 and its receptors are correlated with oncogenic activity of this cytokine. In early stages of BC this cytokine inhibits epithelial cell cycle progression and promotes apoptosis, showing tumor suppressive effects. However, in late stages, TGF-β1 is linked with increased tumor progression, higher cell motility, cancer invasiveness, and metastasis. It is also involved in cancer microenvironment modification and promotion of epithelial to mesenchymal transition (EMT). This review summarizes the current knowledge on the phenomenon called “TGF-β1 paradox”, showing that better understanding of TGF-β1 functions can be a step towards development of new therapeutic approaches. According to current knowledge several drugs against TGF-β1 have been developed and are either in nonclinical or in early stages of clinical investigation.

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The Emerging Role of MicroRNAs in Regulating the Drug Response of Cholangiocarcinoma

Biomolecules ◽

10.3390/biom10101396 ◽

2020 ◽

Vol 10 (10) ◽

pp. 1396

Author(s):

Wen-Kuan Huang ◽

Chun-Nan Yeh

Keyword(s):

Drug Resistance ◽

Targeted Therapy ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Current Knowledge ◽

Treatment Strategies ◽

Standard Of Care ◽

Migration And Invasion ◽

Transcriptional Level ◽

Mesenchymal Transition

Cholangiocarcinoma (CCA) is the most common biliary malignancy, and has a poor prognosis. The median overall survival with the standard-of-care chemotherapy (Gemcitabine and cisplatin) in patients with advanced-stage CCA is less than one year. The limited efficacy of chemotherapy or targeted therapy remains a major obstacle to improving survival. The mechanisms involved in drug resistance are complex. Research efforts focusing on the distinct molecular mechanisms underlying drug resistance should prompt the development of treatment strategies that overcome chemoresistance or targeted drug resistance. MicroRNAs (miRNAs) are a class of evolutionarily conserved, short noncoding RNAs regulating gene expression at the post-transcriptional level. Dysregulated miRNAs have been shown to participate in almost all CCA hallmarks, including cell proliferation, migration and invasion, apoptosis, and the epithelial-to-mesenchymal transition. Emerging evidence demonstrates that miRNAs play a role in regulating responses to chemotherapy and targeted therapy. Herein, we present an overview of the current knowledge on the miRNA-mediated regulatory mechanisms underlying drug resistance among CCA. We also discuss the application of miRNA-based therapeutics to CCA, providing the basis for innovative treatment approaches.

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Standard of Care and Promising New Agents for the Treatment of Mesenchymal Triple-Negative Breast Cancer

Cancers ◽

10.3390/cancers13051080 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1080

Author(s):

Silvia Mezi ◽

Andrea Botticelli ◽

Giulia Pomati ◽

Bruna Cerbelli ◽

Simone Scagnoli ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Epithelial To Mesenchymal Transition ◽

Triple Negative ◽

Current Knowledge ◽

Standard Of Care ◽

Transition Process ◽

Breast Cancer Patients ◽

Mesenchymal Transition ◽

Expression Of Genes

The pathologic definition of triple negative breast cancer (TNBC) relies on the absence of expression of estrogen, progesterone and HER2 receptors. However, this BC subgroup is distinguished by a wide biological, molecular and clinical heterogeneity. Among the intrinsic TNBC subtypes, the mesenchymal type is defined by the expression of genes involved in the epithelial to mesenchymal transition, stromal interaction and cell motility. Moreover, it shows a high expression of genes involved in proliferation and an immune-suppressive microenvironment. Several molecular alterations along different pathways activated during carcinogenesis and tumor progression have been outlined and could be involved in immune evasion mechanisms. Furthermore, reverting epithelial to mesenchymal transition process could lead to the overcoming of immune-resistance. This paper reviews the current knowledge regarding the mesenchymal TNBC subtype and its response to conventional therapeutic strategies, as well as to some promising molecular target agents and immunotherapy. The final goal is a tailored combination of cytotoxic drugs, target agents and immunotherapy in order to restore immunocompetence in mesenchymal breast cancer patients.

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Identification of TAZ-Dependent Breast Cancer Vulnerabilities Using a Chemical Genomics Screening Approach

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.673374 ◽

2021 ◽

Vol 9 ◽

Author(s):

He Shen ◽

Yanmin Chen ◽

Yin Wan ◽

Tao Liu ◽

Jianmin Wang ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Cells ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Therapy Resistance ◽

Chemotherapeutic Agents ◽

Binding Motif ◽

Metastatic Progression ◽

Tumor Seeding ◽

Mesenchymal Transition

Breast cancer stem cells (BCSCs) represent a subpopulation of tumor cells that can self-renew and generate tumor heterogeneity. Targeting BCSCs may ameliorate therapy resistance, tumor growth, and metastatic progression. However, the origin and molecular mechanisms underlying their cellular properties are poorly understood. The transcriptional coactivator with PDZ-binding motif (TAZ) promotes mammary stem/progenitor cell (MaSC) expansion and maintenance but also confers stem-like traits to differentiated tumor cells. Here, we describe the rapid generation of experimentally induced BCSCs by TAZ-mediated reprogramming of human mammary epithelial cells, hence allowing for the direct analysis of BCSC phenotypes. Specifically, we establish genetically well-defined TAZ-dependent (TAZDEP) and -independent (TAZIND) cell lines with cancer stem cell (CSC) traits, such as self-renewal, variable resistance to chemotherapeutic agents, and tumor seeding potential. TAZDEP cells were associated with the epithelial to mesenchymal transition, embryonic, and MaSC signature genes. In contrast, TAZIND cells were characterized by a neuroendocrine transdifferentiation transcriptional program associated with Polycomb repressive complex 2 (PRC2). Mechanistically, we identify Cyclin D1 (CCND1) as a critical downstream effector for TAZ-driven tumorigenesis. Overall, our results reveal a critical TAZ-CCND1-CDK4/CDK6 signaling axis, suggesting novel therapeutic approaches to eliminate both BCSCs and therapy-resistant cancer cells.

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SMAD4 and the TGFβ Pathway in Patients with Pancreatic Ductal Adenocarcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms21103534 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3534

Author(s):

Julie Dardare ◽

Andréa Witz ◽

Jean-Louis Merlin ◽

Pauline Gilson ◽

Alexandre Harlé

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Transforming Growth Factor ◽

Current Knowledge ◽

Ductal Adenocarcinoma ◽

Tgfβ Signaling ◽

Potent Inducer ◽

Mesenchymal Transition ◽

Tgfβ Pathway

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death worldwide. PDAC is an aggressive disease with an 11-month median overall survival and a five-year survival of less than 5%. Incidence of PDAC is constantly increasing and is predicted to become the second leading cause of cancer in Western countries within a decade. Despite research and therapeutic development, current knowledge about PDAC molecular mechanisms still needs improvements and it seems crucial to identify novel therapeutic targets. Genomic analyses of PDAC revealed that transforming growth factor β (TGFβ) signaling pathways are modified and the SMAD4 gene is altered in 47% and 60% of cases, respectively, highlighting their major roles in PDAC development. TGFβ can play a dual role in malignancy depending on the context, sometimes as an inhibitor and sometimes as an inducer of tumor progression. TGFβ signaling was identified as a potent inducer of epithelial-to-mesenchymal transition (EMT), a process that confers migratory and invasive properties to epithelial cells during cancer. Therefore, aberrant TGFβ signaling and EMT are linked to promoting PDAC aggressiveness. TGFβ and SMAD pathways were extensively studied but the mechanisms leading to cancer promotion and development still remain unclear. This review aims to describe the complex role of SMAD4 in the TGFβ pathway in patients with PDAC.

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The Recruitment of Neutrophils to the Tumor Microenvironment Is Regulated by Multiple Mediators

Frontiers in Immunology ◽

10.3389/fimmu.2021.734188 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shuvasree SenGupta ◽

Lauren E. Hein ◽

Carole A. Parent

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Current Knowledge ◽

Extracellular Vesicle ◽

Immune Defense ◽

Mesenchymal Transition ◽

Chemotactic Factors

Neutrophils sense and migrate towards chemotactic factors released at sites of infection/inflammation and contain the affected area using a variety of effector mechanisms. Aside from these established immune defense functions, neutrophils are emerging as one of the key tumor-infiltrating immune cells that influence cancer progression and metastasis. Neutrophil recruitment to the tumor microenvironment (TME) is mediated by multiple mediators including cytokines, chemokines, lipids, and growth factors that are secreted from cancer cells and cancer-associated stromal cells. However, the molecular mechanisms that underlie the expression and secretion of the different mediators from cancer cells and how neutrophils integrate these signals to reach and invade tumors remain unclear. Here, we discuss the possible role of the epithelial to mesenchymal transition (EMT) program, which is a well-established promoter of malignant potential in cancer, in regulating the expression and secretion of these key mediators. We also summarize and review our current understanding of the machineries that potentially control the secretion of the mediators from cancer cells, including the exocytic trafficking pathways, secretory autophagy, and extracellular vesicle-mediated secretion. We further reflect on possible mechanisms by which different mediators collaborate by integrating their signaling network, and particularly focus on TGF-β, a cytokine that is highly expressed in invasive tumors, and CXCR2 ligands, which are crucial neutrophil recruiting chemokines. Finally, we highlight gaps in the field and the need to expand current knowledge of the secretory machineries and cross-talks among mediators to develop novel neutrophil targeting strategies as effective therapeutic options in the treatment of cancer.

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Molecular regulation of Snai2 in development and disease

Journal of Cell Science ◽

10.1242/jcs.235127 ◽

2019 ◽

Vol 132 (23) ◽

Author(s):

Wenhui Zhou ◽

Kayla M. Gross ◽

Charlotte Kuperwasser

Keyword(s):

Transcription Factor ◽

Cell Biology ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Zinc Finger Protein ◽

Main Role ◽

Biological Processes ◽

Developmental Defects ◽

Mesenchymal Transition ◽

Damage Repair

ABSTRACT The transcription factor Snai2, encoded by the SNAI2 gene, is an evolutionarily conserved C2H2 zinc finger protein that orchestrates biological processes critical to tissue development and tumorigenesis. Initially characterized as a prototypical epithelial-to-mesenchymal transition (EMT) transcription factor, Snai2 has been shown more recently to participate in a wider variety of biological processes, including tumor metastasis, stem and/or progenitor cell biology, cellular differentiation, vascular remodeling and DNA damage repair. The main role of Snai2 in controlling such processes involves facilitating the epigenetic regulation of transcriptional programs, and, as such, its dysregulation manifests in developmental defects, disruption of tissue homeostasis, and other disease conditions. Here, we discuss our current understanding of the molecular mechanisms regulating Snai2 expression, abundance and activity. In addition, we outline how these mechanisms contribute to disease phenotypes or how they may impact rational therapeutic targeting of Snai2 dysregulation in human disease.

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Operative ubiquitin-specific protease 22 deubiquitination confers a more invasive phenotype to cholangiocarcinoma

Cell Death and Disease ◽

10.1038/s41419-021-03940-0 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Yu Tian ◽

Bo Tang ◽

Chengye Wang ◽

Yan Wang ◽

Jiakai Mao ◽

...

Keyword(s):

Tumour Growth ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Sirtuin 1 ◽

Mesenchymal Transition ◽

Specific Protease ◽

Ubiquitin Specific Protease ◽

Paired Tumour

AbstractOncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-β-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.

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Proteomic Analysis of Zeb1 Interactome in Breast Carcinoma Cells

Molecules ◽

10.3390/molecules26113143 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3143

Author(s):

Sergey E. Parfenyev ◽

Sergey V. Shabelnikov ◽

Danila Y. Pozdnyakov ◽

Olga O. Gnedina ◽

Leonid S. Adonin ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Critical Role ◽

Malignant Neoplasm ◽

Malignant Neoplasms ◽

Breast Cancer Patients ◽

Survival Prognosis ◽

Mesenchymal Transition ◽

Wide Range

Breast cancer is the most frequently diagnosed malignant neoplasm and the second leading cause of cancer death among women. Epithelial-to-mesenchymal Transition (EMT) plays a critical role in the organism development, providing cell migration and tissue formation. However, its erroneous activation in malignancies can serve as the basis for the dissemination of cancer cells and metastasis. The Zeb1 transcription factor, which regulates the EMT activation, has been shown to play an essential role in malignant transformation. This factor is involved in many signaling pathways that influence a wide range of cellular functions via interacting with many proteins that affect its transcriptional functions. Importantly, the interactome of Zeb1 depends on the cellular context. Here, using the inducible expression of Zeb1 in epithelial breast cancer cells, we identified a substantial list of novel potential Zeb1 interaction partners, including proteins involved in the formation of malignant neoplasms, such as ATP-dependent RNA helicase DDX17and a component of the NURD repressor complex, CTBP2. We confirmed the presence of the selected interactors by immunoblotting with specific antibodies. Further, we demonstrated that co-expression of Zeb1 and CTBP2 in breast cancer patients correlated with the poor survival prognosis, thus signifying the functionality of the Zeb1–CTBP2 interaction.

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