The Advancing Roles of Exosomes in Breast Cancer

Breast cancer (BC) develops from breast tissue and is the most common aggressive malignant tumor in women worldwide. Although advanced treatment strategies have been applied and reduced current mortality rates, BC control remains unsatisfactory. It is essential to elucidate the underlying molecular mechanisms to assist clinical options. Exosomes are a type of extracellular vesicles and mediate cellular communications by delivering various biomolecules (oncogenes, oncomiRs, proteins, and even pharmacological compounds). These bioactive molecules can be transferred to change the transcriptome of target cells and influence tumor-related signaling pathways. Extensive studies have implicated exosomes in BC biology, including therapeutic resistance and the surrounding microenvironment. This review focuses on discussing the functions of exosomes in tumor treatment resistance, invasion and metastasis of BC. Moreover, we will also summarize multiple interactions between exosomes and the BC tumor microenvironment. Finally, we propose promising clinical applications of exosomes in BC.

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Baicalein Suppresses Stem Cell-Like Characteristics in Radio- and Chemoresistant MDA-MB-231 Human Breast Cancer Cells through Up-Regulation of IFIT2

Nutrients ◽

10.3390/nu11030624 ◽

2019 ◽

Vol 11 (3) ◽

pp. 624 ◽

Cited By ~ 13

Author(s):

So Koh ◽

Jeong Moon ◽

Tatsuya Unno ◽

Somi Cho

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Molecular Mechanisms ◽

Side Population ◽

Acquired Resistance ◽

Treatment Resistance ◽

Toll Like Receptor ◽

Tetratricopeptide Repeats ◽

Mammosphere Formation ◽

Induced Apoptosis

Resistance to both chemotherapy and radiation therapy is frequent in triple-negative breast cancer (TNBC) patients. We established treatment-resistant TNBC MDA-MB-231/IR cells by irradiating the parental MDA-MB-231 cells 25 times with 2 Gy irradiation and investigated the molecular mechanisms of acquired resistance. The resistant MDA-MB-231/IR cells were enhanced in migration, invasion, and stem cell-like characteristics. Pathway analysis by the Database for Annotation, Visualization and Integrated Discovery revealed that the NF-κB pathway, TNF signaling pathway, and Toll-like receptor pathway were enriched in MDA-MB-231/IR cells. Among 77 differentially expressed genes revealed by transcriptome analysis, 12 genes involved in drug and radiation resistance, including interferon-induced protein with tetratricopeptide repeats 2 (IFIT2), were identified. We found that baicalein effectively reversed the expression of IFIT2, which is reported to be associated with metastasis, recurrence, and poor prognosis in TNBC patients. Baicalein sensitized radio- and chemoresistant cells and induced apoptosis, while suppressing stem cell-like characteristics, such as mammosphere formation, side population, expression of Oct3/4 and ABCG2, and CD44highCD24low population in MDA-MB-231/IR cells. These findings improve our understanding of the genes implicated in radio- and chemoresistance in breast cancer, and indicate that baicalein can serve as a sensitizer that overcomes treatment resistance.

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Pathophysiological roles of ERα in the ER signaling mediated oncogenesis of breast cancer

European Journal of Clinical and Experimental Medicine ◽

10.15584/ejcem.2020.4.6 ◽

2021 ◽

Vol 18 (4) ◽

pp. 289-302

Author(s):

Sultan Abda Neja ◽

Keyword(s):

Breast Cancer ◽

Estrogen Receptor Alpha ◽

Breast Tissue ◽

Transcriptional Activity ◽

Review Literature ◽

Bibliographic Databases ◽

Target Cells ◽

Breast Cancers ◽

Oncogenic Pathways ◽

Estradiol 17Β

Introduction. Estrogen receptors (ER) are members of nuclear receptors that act in the ER signaling pathway regulating the pathophysiology of hormone-responsive target cells including breast tissue. Aim. This detailled review literature was written on the pathophysiology of ER signaling as well as the effect altered ERα and associated pathway derangement in the oncogenesis of breast cancer. Material and methods. This review was performed according to systematic literature search of three major bibliographic databases (Scopus, PubMed, and Cochran). Analysis of the literature. In this pathway, estrogen receptor alpha (ERα) is a key estradiol-17β (E2) induced transcription factor that has been implicated in the initiation and development of the major fraction of breast cancers. Hence understanding the ERα-mediated ER signaling that results in alterations from normal phenotypic features of breast tissue to the oncogenic features of breast cancer is important. The oncogenic effect of ERα in ER signaling is driven by combinations of molecular assets within the cancer cells. Normally, the transcriptional activity of ERα is controlled by tight regulation of its protein level inside the cells. Altered stability and activity of ERα due to its phosphorylation, ubiquitination, glycosylation, sumoylation, and acetylation events can trigger oncogenic ER signaling. Conclusion. The function and activity of ERα is also modulated by its interaction with coregulators as well as crosstalk with oncogenic factors from other oncogenic pathways. These all events increase the complexity of the progression of ER+ breast cancer and its response to endocrine therapy.

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Adipocytes and microRNAs Crosstalk: A Key Tile in the Mosaic of Breast Cancer Microenvironment

Cancers ◽

10.3390/cancers11101451 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1451 ◽

Cited By ~ 7

Author(s):

Erika Bandini ◽

Tania Rossi ◽

Giulia Gallerani ◽

Francesco Fabbri

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Immune Cells ◽

Tumor Suppressor Genes ◽

Breast Tissue ◽

Molecular Mechanisms ◽

Important Target ◽

New Concepts ◽

Clinical Strategies

Breast cancer (BC) is a disease characterized by a high grade of heterogeneity. Consequently, despite the great achievements obtained in the last decades, most of the current therapeutic regimens still fail. The identification of new molecular mechanisms that will increase the knowledge of all steps of tumor initiation and growth is mandatory in finding new clinical strategies. The BC microenvironment, consisting of endothelial cells, fibroblasts, immune cells and adipocytes, plays an essential role in regulating BC development, and recently it has gained great attention in the scientific community. In particular, adipose tissue is emerging as an important target to investigate among mammary gland components. The mechanisms underlying BC progression driven by adipocytes are predominantly unexplored, especially that involving the switch from normal adipocytes to the so-called cancer-associated adipocytes (CAAs). MicroRNAs (miRNAs), a class of gene expression modulators, have emerged as the regulators of key oncogenes and tumor suppressor genes that affect multiple pathways of the tumor microenvironment and adipose tissue. This review concerns a presentation of the role of adipocytes in breast tissue, and describes the most recent discoveries about the interplay between adipocytes and miRNAs, which collaborate in the arrangement of a pro-inflammatory and cancerous microenvironment, laying the foundations for new concepts in the prevention and treatment of BC.

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Inhibition of PLOD3 Suppresses Proliferation, Invasion and Migration of Breast Cancer Cells

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2019.2171 ◽

2019 ◽

Vol 9 (11) ◽

pp. 1528-1534

Author(s):

Shiqiong Su ◽

Qing Ni ◽

Jing Hou

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Western Blotting ◽

Molecular Mechanisms ◽

Treatment Strategies ◽

Cell Counting ◽

Matrix Metalloproteinase 2 ◽

Invasion And Migration ◽

And Migration ◽

Interfering Rna

Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) has been reported to be involved in various human cancers. However, the function of PLOD3 in breast cancer (BC) has not been addressed. This research attempted to probe the effects and molecular mechanisms of PLOD3 in BC. The expression of PLOD3 was examined by Western blotting and RT-qPCR in several BC cell lines and nontumorigenic breast MCF-10A cells. Then, PLOD3 was silenced by transfecting with small interfering RNA (siRNA). Cell proliferation was measured by Cell Counting Kit-8 assay and cell cycle was evaluated by flow cytometry assay after transfection. Subsequently, wound healing assay and Transwell assay were exploited for detecting the abilities of cell invasion and migration, respectively. In addition, the expression of proliferation- and migration-related genes were examined by Western blotting. The results revealed that the expression of PLOD3 was upregulated in BC cell lines compared with MCF-10A cells. PLOD3 silencing suppressed the proliferative ability of BC cells, enhanced the ratio of cells in the G1 and G2 phases and reduced those in the S phase. Moreover, the expression of Ki67 and cyclinD1 were significantly downregulated, accompanied by an upregulation in p27 expression after transfection with PLOD3 siRNA. Furthermore, inhibition of PLOD3 restrained invasion and migration of BC cells coupled with a reduced expression of matrix metalloproteinase 2 (MMP2) and MMP9. The explorations unveiled that PLOD3 silencing restrained proliferation, invasion and migration of BC cells, which provides theoretical basis and treatment strategies for the treatment of BC.

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Dynamics of Breast Cancer under Different Rates of Chemoradiotherapy

Computational and Mathematical Methods in Medicine ◽

10.1155/2019/5216346 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Sara B. Mkango ◽

Nyimvua Shaban ◽

Eunice Mureithi ◽

Twalib Ngoma

Keyword(s):

Breast Cancer ◽

Gene Therapy ◽

Decay Rate ◽

Hormone Therapy ◽

Cause Of Death ◽

Breast Tissue ◽

Treatment Strategies ◽

Common Cause ◽

New Treatment ◽

Treat Breast Cancer

A type of cancer which originates from the breast tissue is referred to as breast cancer. Globally, it is the most common cause of death in women. Treatments such as radiotherapy, chemotherapy, hormone therapy, immunotherapy, and gene therapy are the main strategies in the fight against breast cancer. The present study aims at investigating the effects of the combined radiotherapy and chemotherapy as a way to treat breast cancer, and different treatment approaches are incorporated into the model. Also, the model is fitted to data on patients with breast cancer in Tanzania. We determine new treatment strategies, and finally, we show that when sufficient amount of chemotherapy and radiotherapy with a low decay rate is used, the drug will be significantly more effective in combating the disease while health cells remain above the threshold.

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Cisplatin-resistant triple-negative breast cancer subtypes: multiple mechanisms of resistance

BMC Cancer ◽

10.1186/s12885-019-6278-9 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 12

Author(s):

David P. Hill ◽

Akeena Harper ◽

Joan Malcolm ◽

Monica S. McAndrews ◽

Susan M. Mockus ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Molecular Mechanisms ◽

Triple Negative ◽

Treatment Strategies ◽

Heterogeneous Data ◽

Variable Response ◽

Mechanisms Of Resistance ◽

Mesenchymal Transition ◽

Cancer Subtypes

Abstract Background Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies. Methods In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated genes, evaluating their differential expression in the cisplatin-sensitive, basal-like 1 (BL1) and basal-like 2 (BL2) subtypes, and the two cisplatin-resistant, luminal androgen receptor (LAR) and mesenchymal (M) subtypes of TNBC. Results We found 20 genes that were differentially expressed in at least one subtype. Fifteen of the 20 genes are associated with cell death and are distributed among all TNBC subtypes. The less cisplatin-responsive LAR and M TNBC subtypes show different regulation of 13 genes compared to the more sensitive BL1 and BL2 subtypes. These 13 genes identify a variety of cisplatin-resistance mechanisms including increased transport and detoxification of cisplatin, and mis-regulation of the epithelial to mesenchymal transition. Conclusions We identified gene signatures in resistant TNBC subtypes indicative of mechanisms of cisplatin. Our results indicate that response to cisplatin in TNBC has a complex foundation based on impact of treatment on distinct cellular pathways. We find that examination of expression data in the context of heterogeneous data such as drug-gene interactions leads to a better understanding of mechanisms at work in cancer therapy response.

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Breast Cancer Stem Cell-Derived ANXA6-Containing Exosomes Sustain Paclitaxel Resistance and Cancer Aggressiveness in Breast Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.718721 ◽

2021 ◽

Vol 9 ◽

Author(s):

Zihe Guo ◽

Ayao Guo ◽

Chuang Zhou

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Hippo Pathway ◽

Treatment Strategies ◽

Dependent Manner ◽

Promote Cell Migration ◽

Cancer Aggressiveness ◽

Novel Treatment Strategies ◽

Underlying Mechanisms

Continuous chemotherapy pressure-elicited annexin-A6 (ANXA6)-containing exosome (ANXA6-exo) secretion contributes to paclitaxel (PTX) resistance in breast cancer (BC), but the molecular mechanisms are not fully elucidated. The present study managed to investigate this issue and found that ANXA6-exo promoted PTX resistance and cancer progression in BC cells in a Yes-associated protein 1 (YAP1)-dependent manner. Specifically, the parental PTX-sensitive BC (PS-BC) cells were exposed to continuous low-dose PTX to generate PTX-resistant BC (PR-BC) cells, and we found that BC stem cells tended to be enriched in the descendent PR-BC cells in contrast with the PS-BC cells. In addition, PR-BC cell-derived exosomes were featured with highly expressed ANXA6, and ANXA6-exo delivered ANXA6 to promote cell migration, growth, autophagy, and stemness in PS-BC cells. Interestingly, ANXA6-exo increased PTX resistance in PS-BC cells via inducing autophagy, and the effects of ANXA6-exo on PTX resistance in PS-BC cells were abrogated by co-treating cells with the autophagy inhibitor 3-methyladenine. Moreover, the underlying mechanisms were uncovered, and we evidenced that ANXA6-exo up-regulated YAP1 to promote Hippo pathway dysregulation, and the promoting effects of ANXA6-exo on PTX resistance and cancer aggressiveness in BC cells were abrogated by silencing YAP1. Taken together, this study firstly elucidated the underlying mechanisms by which BCSC-derived ANXA6-exo facilitated BC progression and PTX resistance, which might help to develop novel treatment strategies for BC in clinic.

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Expressions and Prognostic Values of LPARs in Human Breast Cancer

10.21203/rs.3.rs-144766/v1 ◽

2021 ◽

Author(s):

Tao Wang ◽

Kai Sun ◽

Zhanxiong Luo ◽

Rixin Chen ◽

Jingzhang Li

Keyword(s):

Breast Cancer ◽

Mrna Expression ◽

Survival Data ◽

Breast Tissue ◽

Molecular Mechanisms ◽

Normal Breast Tissue ◽

Normal Breast ◽

Expression Levels ◽

Lpa Receptors ◽

New Biomarkers

Abstract Background: LPA and its receptors play a major role in adjusting malignant behaviors in breast cancer (BC). Abnormal expression of certain LPA receptors in BC indicate that LPA receptors could be novel potential biomarkers in predicting prognosis and progression of BC. Further studies would focus on molecular mechanisms of LPA receptors in BC.Results: In this study, we examined the transcription and survival data of BC patient LPARs from ONCOMINE, Kaplan-Meier plotter, GEPIA, bcGenEx-Miner and cBioPortal database. We revealed that LPAR2/3/5 expression levels in BC tissue were higher than that in normal breast tissue, whereas the expression levels of LPAR1/4/6 in BC tissue were lower than normal breast tissue. The expression levels of LPAR1/4/6 were associated with advanced-stage tumor. Survival analysis using the K-M plotter database showed that in all BC patients, high mRNA expression of LPAR1/4/5/6 and the low mRNA expression of LPAR2/3 were correlated with the improved outcomes of BC patients. Subgroup analyses based on clinicopathological factors further revealed relationship between the expression levels of LPARs and the prognosis of BC patients with different types.Conclusions: This study shows that LPAR2/3/5 are potential targets for precision treatment of BC patients, and six LPARs are new biomarkers for the prognosis of BC patients.

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Exosomes are the Driving Force in Preparing the Soil for the Metastatic Seeds: Lessons from the Prostate Cancer

Cells ◽

10.3390/cells9030564 ◽

2020 ◽

Vol 9 (3) ◽

pp. 564 ◽

Cited By ~ 4

Author(s):

Saber H. Saber ◽

Hamdy E. A. Ali ◽

Rofaida Gaballa ◽

Mohamed Gaballah ◽

Hamed I. Ali ◽

...

Keyword(s):

Prostate Cancer ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Membrane Vesicles ◽

Cell Types ◽

Bioactive Molecules ◽

Therapeutic Interventions ◽

Target Cells ◽

Molecular Signatures ◽

Cellular Processes

Exosomes are nano-membrane vesicles that various cell types secrete during physiological and pathophysiological conditions. By shuttling bioactive molecules such as nucleic acids, proteins, and lipids to target cells, exosomes serve as key regulators for multiple cellular processes, including cancer metastasis. Recently, microvesicles have emerged as a challenge in the treatment of prostate cancer (PCa), encountered either when the number of vesicles increases or when the vesicles move into circulation, potentially with an ability to induce drug resistance, angiogenesis, and metastasis. Notably, the exosomal cargo can induce the desmoplastic response of PCa-associated cells in a tumor microenvironment (TME) to promote PCa metastasis. However, the crosstalk between PCa-derived exosomes and the TME remains only partially understood. In this review, we provide new insights into the metabolic and molecular signatures of PCa-associated exosomes in reprogramming the TME, and the subsequent promotion of aggressive phenotypes of PCa cells. Elucidating the molecular mechanisms of TME reprogramming by exosomes draws more practical and universal conclusions for the development of new therapeutic interventions when considering TME in the treatment of PCa patients.

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Honeybee venom and melittin suppress growth factor receptor activation in HER2-enriched and triple-negative breast cancer

npj Precision Oncology ◽

10.1038/s41698-020-00129-0 ◽

2020 ◽

Vol 4 (1) ◽

Cited By ~ 2

Author(s):

Ciara Duffy ◽

Anabel Sorolla ◽

Edina Wang ◽

Emily Golden ◽

Eleanor Woodward ◽

...

Keyword(s):

Breast Cancer ◽

Plasma Membrane ◽

Anticancer Agents ◽

Molecular Mechanisms ◽

Triple Negative ◽

Treatment Strategies ◽

Receptor Activation ◽

Breast Cancers ◽

Honeybee Venom ◽

Cancer Subtypes

Abstract Despite decades of study, the molecular mechanisms and selectivity of the biomolecular components of honeybee (Apis mellifera) venom as anticancer agents remain largely unknown. Here, we demonstrate that honeybee venom and its major component melittin potently induce cell death, particularly in the aggressive triple-negative and HER2-enriched breast cancer subtypes. Honeybee venom and melittin suppress the activation of EGFR and HER2 by interfering with the phosphorylation of these receptors in the plasma membrane of breast carcinoma cells. Mutational studies reveal that a positively charged C-terminal melittin sequence mediates plasma membrane interaction and anticancer activity. Engineering of an RGD motif further enhances targeting of melittin to malignant cells with minimal toxicity to normal cells. Lastly, administration of melittin enhances the effect of docetaxel in suppressing breast tumor growth in an allograft model. Our work unveils a molecular mechanism underpinning the anticancer selectivity of melittin, and outlines treatment strategies to target aggressive breast cancers.

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