Molecular Mechanisms of Loss of β2-Microglobulin Expression in Drug-Resistant Breast Cancer Sublines and Its Involvement in Drug Resistance†

Background: We investigated molecular mechanisms behind astaxanthinmediated induction of apoptosis in breast cancer cell lines toward combination therapy against cancer drug resistance. Methods: Breast cancer cell lines were treated with serial concentrations of astaxanthin to determine its IC50. We used drug-design software to predict interactions between astaxanthin and receptor tyrosine kinases or other key gene products involved in intracellular signaling pathways. Changes in gene expression were examined using RT-PCR. The effect of astaxanthin-nanocarbons combinations on cancer cells was also evaluated. Results: Astaxanthin induced cell death in all three breast cancer cell lines was examined so that its IC50 in two HER2-amplifying lines SKBR3 and BT-474 stood, respectively, at 36 and 37 ?M; however, this figure for MCF-7 was significantly lowered to 23 ?M (P<0.05). Astaxanthin-treated SKBR3 cells showed apoptotic death upon co-staining. Our in silico examinations showed that some growth-promoting molecules are strongly bound by astaxanthin via their specific amino acid residues with their binding energy standing below -6 KCa/Mol. Next, astaxanthin was combined with either graphene oxide or carboxylated multi-walled carbon nanotube, with the latter affecting SKBR cell survival more extensively than the former (P<0.05). Finally, astaxanthin coinduced tumor suppressors p53 and PTEN but downregulated the expression of growth-inducing genes in treated cells. Conclusion: These findings indicate astaxanthin carries' multitarget antitumorigenic capacities and introduce the compound as a suitable candidate for combination therapy regimens against cancer growth and drug resistance. Development of animal models to elucidate interactions between the compound and tumor microenvironment could be a major step forward towards the inclusion of astaxanthin in cancer therapy trials.

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The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future

Cancers ◽

10.3390/cancers13184576 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4576

Author(s):

Hung-Yu Lin ◽

Hui-Wen Ho ◽

Yen-Hsiang Chang ◽

Chun-Jui Wei ◽

Pei-Yi Chu

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Drug Resistant ◽

Therapeutic Targeting ◽

The Past ◽

Regulated Cell Death ◽

Common Malignancy

Breast cancer (BC) is the most common malignancy among women worldwide. The discovery of regulated cell death processes has enabled advances in the treatment of BC. In the past decade, ferroptosis, a new form of iron-dependent regulated cell death caused by excessive lipid peroxidation has been implicated in the development and therapeutic responses of BC. Intriguingly, the induction of ferroptosis acts to suppress conventional therapy-resistant cells, and to potentiate the effects of immunotherapy. As such, pharmacological or genetic modulation targeting ferroptosis holds great potential for the treatment of drug-resistant cancers. In this review, we present a critical analysis of the current understanding of the molecular mechanisms and regulatory networks involved in ferroptosis, the potential physiological functions of ferroptosis in tumor suppression, its potential in therapeutic targeting, and explore recent advances in the development of therapeutic strategies for BC.

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Quercetin Inhibits Lef1 and Resensitizes Docetaxel-Resistant Breast Cancer Cells

Molecules ◽

10.3390/molecules25112576 ◽

2020 ◽

Vol 25 (11) ◽

pp. 2576 ◽

Cited By ~ 1

Author(s):

Marta Prieto-Vila ◽

Iwao Shimomura ◽

Akiko Kogure ◽

Wataru Usuba ◽

Ryou-u Takahashi ◽

...

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Metastatic Breast ◽

Drug Resistant ◽

Breast Cancer Patients ◽

Phase I Clinical Trials ◽

Pathway Activation ◽

Promising Therapeutic Approach ◽

Cav1 Expression ◽

Resistant Cells

Drug resistance is a major problem for breast cancer patients. Docetaxel is an anti-mitotic agent that serves as first line of treatment in metastatic breast cancer, however it is susceptible to cellular drug resistance. Drug-resistant cells are able to spread during treatment, leading to treatment failure and eventually metastasis, which remains the main cause for cancer-associated death. In previous studies, we used single-cell technologies and identified a set of genes that exhibit increased expression in drug-resistant cells, and they are mainly regulated by Lef1. Furthermore, upregulating Lef1 in parental cells caused them to become drug resistant. Therefore, we hypothesized that inhibiting Lef1 could resensitize cells to docetaxel. Here, we confirmed that Lef1 inhibition, especially on treatment with the small molecule quercetin, decreased the expression of Lef1 and resensitized cells to docetaxel. Our results demonstrate that Lef1 inhibition also downregulated ABCG2, Vim, and Cav1 expression and equally decreased Smad-dependent TGF-β signaling pathway activation. Likewise, these two molecules worked in a synergetic manner, greatly reducing the viability of drug-resistant cells. Prior studies in phase I clinical trials have already shown that quercetin can be safely administered to patients. Therefore, the use of quercetin as an adjuvant treatment in addition to docetaxel for the treatment of breast cancer may be a promising therapeutic approach.

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Vitamin D-Induced Molecular Mechanisms to Potentiate Cancer Therapy and to Reverse Drug-Resistance in Cancer Cells

Nutrients ◽

10.3390/nu12061798 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1798 ◽

Cited By ~ 5

Author(s):

Mariarosaria Negri ◽

Annalisa Gentile ◽

Cristina de Angelis ◽

Tatiana Montò ◽

Roberta Patalano ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Vitamin D ◽

Drug Resistance ◽

Cancer Therapy ◽

Cancer Stem Cells ◽

Crucial Role ◽

Molecular Mechanisms ◽

Vitamin D Supplementation

Increasing interest in studying the role of vitamin D in cancer has been provided by the scientific literature during the last years, although mixed results have been reported. Vitamin D deficiency has been largely associated with various types of solid and non-solid human cancers, and the almost ubiquitous expression of vitamin D receptor (VDR) has always led to suppose a crucial role of vitamin D in cancer. However, the association between vitamin D levels and the risk of solid cancers, such as colorectal, prostate and breast cancer, shows several conflicting results that raise questions about the use of vitamin D supplements in cancer patients. Moreover, studies on vitamin D supplementation do not always show improvements in tumor progression and mortality risk, particularly for prostate and breast cancer. Conversely, several molecular studies are in agreement about the role of vitamin D in inhibiting tumor cell proliferation, growth and invasiveness, cell cycle arrest and inflammatory signaling, through which vitamin D may also regulate cancer microenvironment through the activation of different molecular pathways. More recently, a role in the regulation of cancer stem cells proliferation and short non-coding microRNA (miRNAs) expression has emerged, conferring to vitamin D a more crucial role in cancer development and progression. Interestingly, it has been shown that vitamin D is able not only to potentiate the effects of traditional cancer therapy but can even contribute to overcome the molecular mechanisms of drug resistance—often triggering tumor-spreading. At this regard, vitamin D can act at various levels through the regulation of growth of cancer stem cells and the epithelial–mesenchymal transition (EMT), as well as through the modulation of miRNA gene expression. The current review reconsiders epidemiological and molecular literature concerning the role of vitamin D in cancer risk and tumor development and progression, as well as the action of vitamin D supplementation in potentiating the effects of drug therapy and overcoming the mechanisms of resistance often triggered during cancer therapies, by critically addressing strengths and weaknesses of available data from 2010 to 2020.

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Biopsy-driven study to identify biomarkers of drug resistance in patients with triple-negative breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.30_suppl.87 ◽

2012 ◽

Vol 30 (30_suppl) ◽

pp. 87-87

Author(s):

Adriana Aguilar-Mahecha ◽

Josiane Lafleur ◽

Elaheh Ahmadzadeh ◽

Ewa Przybytkowski ◽

Carole Seguin ◽

...

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Cell Lines ◽

Triple Negative ◽

Acquired Resistance ◽

Great Difficulty ◽

Clinical Samples ◽

Drug Resistant ◽

Breast Cancers ◽

Breast Cancer Patients

87 Background: Resistance to chemotherapy is the underlying cause of death in most patients dying of breast cancer. Patients with early stages of breast cancer whose tumor is or becomes resistant to chemotherapy have a poor prognosis, while women with advanced breast cancer live as long as their tumors respond to chemotherapy. Because of the great difficulty of obtaining clinical samples from drug resistant tumors in patients, there is scant information about molecular factors from actual drug resistant tumors. This project aims to systematically profile resistant triple negative breast cancers (TNBCs) in order to discover molecular “resistance” genes/proteins as a first step to develop strategies to overcome drug resistance. Methods: Paired biopsies are collected from TNBC patients (NCT01276899). Four needle core biopsies are collected before the initiation of treatment and 2 weeks before surgery or at the time of progression in the neoadjuvant and metastatic settings respectively. Paired biopsies will undergo Next Gen Sequencing, flow sorted aCGH analysis, gene expression and miRNA profiling as well as phosphoproteomic profiling using reverse phase protein arrays. Results: We have currently enrolled 28 patients in the neoadjuvant setting and 3 metastatic patients. We have standardized the methods of collection and processing of tissue and blood specimens to ensure their molecular integrity and compatibility with different genomic and proteomic molecular platforms. Analysis of tumor cellularity has been incorporated into our quality control and we have optimized the extraction of nucleic acids to obtain high yields and optimal quality. In parallel, we have generated acquired resistance to paclitaxel in a panel of TNBC cell lines. These cell lines will also undergo genomic profiling and exome sequencing to identify molecular markers of resistance that will be correlated with the markers found in patient samples. Conclusions: This project will allow us to identify the molecular factors responsible for drug resistance in TNBCs and enable the elaboration of strategies to overcome resistance.

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miR-520h Stimulates Drug Resistance to Paclitaxel by Targeting the OTUD3-PTEN Axis in Breast Cancer

BioMed Research International ◽

10.1155/2020/9512793 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Wenwen Geng ◽

Haiyun Song ◽

Qianqian Zhao ◽

Ke Dong ◽

Qian Pu ◽

...

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Molecular Mechanisms ◽

Target Genes ◽

Ectopic Expression ◽

Cancer Cell Line ◽

Luciferase Reporter ◽

Paclitaxel Resistance ◽

Exact Function ◽

Mcf 7

MicroRNAs (miRNAs) have been identified as negative posttranscriptional regulators of target genes and are involved directly in the pathological processes of tumors, including drug resistance. However, the exact function of miR-520h in breast cancer remains poorly understood. The aim of this study was to investigate the molecular mechanisms of miR-520h in paclitaxel resistance in the MCF-7 breast cancer cell line. Ectopic expression of miR-520h could promote the proliferation of breast cancer cells and inhibit paclitaxel-induced cell apoptosis. Inhibiting the expression of miR-520h could enhance the sensitivity to paclitaxel in paclitaxel-resistant MCF-7/Taxol cells. Furthermore, luciferase reporter assays showed that OTUD3 was a direct target of miR-520h. OTUD3 plays a necessary role in the paclitaxel resistance effect of miR-520h, and cotreatment with a miR-520h inhibitor and OTUD3 overexpression significantly enhanced MCF-7 cell sensitivity to paclitaxel. Moreover, miR-520h substantially inhibited the protein expression of PTEN via OTUD3 and subsequently affected downstream p-AKT pathway activity. In a clinical study, we also found that high miR-520h expression was associated with more aggressive pathological characteristic and poor prognosis. Therefore, our findings showed that miR-520h targeted the OTUD3-PTEN axis to drive paclitaxel resistance, and this miR might be an important potential target for breast cancer treatment.

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Frizzled-7-targeted delivery of zinc oxide nanoparticles to drug-resistant breast cancer cells

Nanoscale ◽

10.1039/c9nr01277j ◽

2019 ◽

Vol 11 (27) ◽

pp. 12858-12870 ◽

Cited By ~ 3

Author(s):

Pakatip Ruenraroengsak ◽

Darya Kiryushko ◽

Ioannis G. Theodorou ◽

Michał M. Klosowski ◽

Erik R. Taylor ◽

...

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Zinc Oxide ◽

Targeted Delivery ◽

Zinc Oxide Nanoparticles ◽

Breast Cancer Cells ◽

Oxide Nanoparticles ◽

Drug Resistant ◽

Cancer Subtypes ◽

Aggressive Breast Cancer

There is a need for novel strategies to treat aggressive breast cancer subtypes and overcome drug resistance.

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3D Bioprinted Drug-Resistant Breast Cancer Spheroids for Quantitative in situ Evaluation of Drug Resistance

Acta Biomaterialia ◽

10.1016/j.actbio.2021.10.031 ◽

2021 ◽

Author(s):

Sera Hong ◽

Joon Myong Song

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Drug Resistant ◽

Cancer Spheroids

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Effect of Dual-Targeting MiR-4282 and ATP-Binding Cassette Sub-Family C Member 4 on Drug Resistance of Breast Cancer Cells and Its Molecular Mechanism

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2020.2289 ◽

2020 ◽

Vol 10 (4) ◽

pp. 507-511

Author(s):

Jie Zhao ◽

Guoqin Jiang

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Molecular Mechanisms ◽

Cell Function ◽

Invasion And Migration ◽

Dual Targeting ◽

And Migration ◽

Mcf 7

Background: The present study focused on the effects of dual-targeting MiR-4282 and ABCC4 on drug resistance of breast cancer cells and the molecular mechanisms, expecting to provide a new approach for treating drug-resistant breast cancer. Material and methods: MiR-4282 overexpression and ABCC4 interference double gene lentiviral vectors were constructed. CCK-8, flow cytometry, Transwell assay and scratch assay were used to determine the overexpression of A and B Group, as well as the expression, proliferation, apoptosis, invasion and migration of C and D Group cells respectively. CCK-8 assay was applied to detect doxorubicin sensitivity. WB was used to detect the expressions of ABCC4, p53 and P-gp proteins in each group. Results: Overexpression of MiR4282 and downregulation of ABCC4 expression inhibited proliferation, invasion and migration of the cells, impeded normal cell cycle progression, and promoted apoptosis of the cells. The effect of dual-targeting MiR-4282 and ABCC4 on cell function is more pronounced. The results of CCK-8 assay showed that overexpression of MiR-4282 and downregulation of ABCC4 expression significantly promoted the sensitivity of MCF-7-ADR to doxorubicin, and dual-targeting MiR-4282 and ABCC4 were sensitive to the cell. The promotion effect is more obvious. WB analysis showed that overexpression of MiR-4282 and downregulation of ABCC4 expression significantly inhibited p53 protein in the cells, plus the inhibitory effects of dual-targeting MiR-4282 and ABCC4 were more obvious. MiR-4282 overexpression could prominently inhibit P-gp protein expression in the cells. Conclusion: Overexpression of MiR-4282 and downregulation of ABCC4 expression inhibit the proliferation, invasion and migration of MCF-7-ADR.

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Mitochondrial dysfunctions trigger the calcium signaling-dependent fungal multidrug resistance

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1911560116 ◽

2019 ◽

Vol 117 (3) ◽

pp. 1711-1721 ◽

Cited By ~ 9

Author(s):

Yeqi Li ◽

Yuanwei Zhang ◽

Chi Zhang ◽

Hongchen Wang ◽

Xiaolei Wei ◽

...

Keyword(s):

Drug Resistance ◽

Multidrug Resistance ◽

Mitochondrial Dysfunction ◽

Calcium Signaling ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Drug Binding ◽

Fitness Cost ◽

Drug Resistant ◽

Resistant Mutants

Drug resistance in fungal pathogens has risen steadily over the past decades due to long-term azole therapy or triazole usage in agriculture. Modification of the drug target protein to prevent drug binding is a major recognized route to induce drug resistance. However, mechanisms for nondrug target-induced resistance remain only loosely defined. Here, we explore the molecular mechanisms of multidrug resistance resulted from an efficient adaptation strategy for survival in drug environments in the human pathogen Aspergillus fumigatus. We show that mutants conferring multidrug resistance are linked with mitochondrial dysfunction induced by defects in heme A biosynthesis. Comparison of the gene expression profiles between the drug-resistant mutants and the parental wild-type strain shows that multidrug-resistant transporters, chitin synthases, and calcium-signaling-related genes are significantly up-regulated, while scavenging mitochondrial reactive oxygen species (ROS)-related genes are significantly down-regulated. The up-regulated-expression genes share consensus calcium-dependent serine threonine phosphatase-dependent response elements (the binding sites of calcium-signaling transcription factor CrzA). Accordingly, drug-resistant mutants show enhanced cytosolic Ca2+ transients and persistent nuclear localization of CrzA. In comparison, calcium chelators significantly restore drug susceptibility and increase azole efficacy either in laboratory-derived or in clinic-isolated A. fumigatus strains. Thus, the mitochondrial dysfunction as a fitness cost can trigger calcium signaling and, therefore, globally up-regulate a series of embedding calcineurin-dependent–response-element genes, leading to antifungal resistance. These findings illuminate how fitness cost affects drug resistance and suggest that disruption of calcium signaling might be a promising therapeutic strategy to fight against nondrug target-induced drug resistance.

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