scholarly journals Mathematical Modeling and Transcriptome Profiling of Breast Cancer Cells During Tamoxifen Treatment Reveal Multiple Trajectories for Resistant Subtypes

2021 ◽  
Author(s):  
Shigeyuki Magi ◽  
Sewon Ki ◽  
Masao Ukai ◽  
Atsuhiko Naito ◽  
Yutaka Suzuki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Metabolic Regulation ◽  
Sequential Analysis ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Transcriptome Profiling ◽  
Tamoxifen Treatment

Abstract Cancer cells acquire drug resistance through following non-resistant, pre-resitant and resistant stages. Although the molecular mechanism of drug resistance is well investigated, the process of drug resistance acquisition remains largely unknown. Here, we elucidate the molecular mechanisms underlying the process of drug resistance acquisition by sequential analysis of gene expression patterns in tamoxifen-treated breast cancer cells. Single-cell RNA-sequencing of tamoxifen-treated cells revealed that tamoxifen-resistant cells can be subgrouped into two, one showing cancer stem cell-like metabolic regulation and the other showing high expression of genes encoding adhesion molecules and histone modifying-enzymes. Pseudotime analyses showed a cell transition trajectory to the two resistant subgroups that stems from shared pre-resistant state. An ordinary differential equation model based on the trajectory fitted well with the experimental results of cell growth. Based on the established model, it was predicted that inhibition of transition to both subtype would be required to prevent the appearance of tamoxifen resistance.

scholarly journals A combination approach of pseudotime analysis and mathematical modeling for understanding drug-resistant mechanisms

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shigeyuki Magi ◽  
Sewon Ki ◽  
Masao Ukai ◽  
Elisa Domínguez-Hüttinger ◽  
Atsuhiko T Naito ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Metabolic Regulation ◽  
Sequential Analysis ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Tamoxifen Resistance ◽  
Equation Model ◽  
Altered Gene

AbstractCancer cells acquire drug resistance through the following stages: nonresistant, pre-resistant, and resistant. Although the molecular mechanism of drug resistance is well investigated, the process of drug resistance acquisition remains largely unknown. Here we elucidate the molecular mechanisms underlying the process of drug resistance acquisition by sequential analysis of gene expression patterns in tamoxifen-treated breast cancer cells. Single-cell RNA-sequencing indicates that tamoxifen-resistant cells can be subgrouped into two, one showing altered gene expression related to metabolic regulation and another showing high expression levels of adhesion-related molecules and histone-modifying enzymes. Pseudotime analysis showed a cell transition trajectory to the two resistant subgroups that stem from a shared pre-resistant state. An ordinary differential equation model based on the trajectory fitted well with the experimental results of cell growth. Based on the established model, it was predicted and experimentally validated that inhibition of transition to both resistant subtypes would prevent the appearance of tamoxifen resistance.

scholarly journals A Combination Approach of Pseudotime Analysis And Mathematical Modeling For Understanding The Drug-Resistant Mechanisms

2021 ◽  
Author(s):  
Shigeyuki Magi ◽  
Sewon Ki ◽  
Masao Ukai ◽  
Elisa Domínguez-Hüttinger ◽  
Atsuhiko Naito ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Metabolic Regulation ◽  
Sequential Analysis ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Tamoxifen Resistance ◽  
Equation Model ◽  
Altered Gene

Abstract Cancer cells acquire drug resistance through the following nonresistant, pre-resistant, and resistant stages. Although the molecular mechanism of drug resistance is well investigated, the process of drug resistance acquisition remains largely unknown. Here we elucidate the molecular mechanisms underlying the process of drug resistance acquisition by sequential analysis of gene expression patterns in tamoxifen-treated breast cancer cells. Single-cell RNA-sequencing indicates that tamoxifen-resistant cells can be subgrouped into two, one showing altered gene expression related to metabolic regulation. The other showed high expression levels of adhesion-related molecules and histone-modifying enzymes. Pseudotime analysis showed a cell transition trajectory to the two resistant subgroups that stem from a shared pre-resistant state. An ordinary differential equation model based on the trajectory fitted well with the experimental results of cell growth. Based on the established model, it was predicted and experimentally validated that inhibition of transition to both resistant subtypes would prevent the appearance of tamoxifen resistance.

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

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.

scholarly journals Corylin sensitizes breast cancer cells to overcome tamoxifen resistance by regulating OAS1/miR-22-3p/SIRT1 axis

2021 ◽  
Author(s):  
Li Che ◽  
Hongru Yang ◽  
Daijie Wang ◽  
Shourong Liu
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Tamoxifen Resistance ◽  
Bioinformatic Analysis ◽  
Mrna Targets ◽  
Direct Target ◽  
Resistant Cells

Breast cancer (BCa) is one of the leading causes of cancer-related death among women worldwide. At present, the clinical treatment with tamoxifen (TAM) is challenged by the development of drug resistance. To investigate the effect of corylin on TAM resistance in BCa cells, this study investigated the molecular mechanisms involving miRNA-mRNA targets modulated by corylin. The TAM-resistant MCF-7TR and T47DTR cell lines were generated, and it was found that corylin treatment reduced the cell viability of these cells significantly. Furthermore, OAS1 was validated to be highly expressed in TAM-resistant cells, while OAS1 knockdown sensitized MCF-7TR and T47DTR cells to TAM treatment. Meanwhile, OAS1 was also repressed by corylin treatment, indicating that OAS1 was a key regulator of corylin function. Through bioinformatic analysis, the tumor suppressive miRNA miR-22-3p was identified to directly target and inhibit OAS1. Moreover, corylin treatment up-regulated miR-22-3p expression, which thus down-regulated the OAS1 expression. Interestingly, OAS1 itself functioned as a miR-22-3p sponge to repress miR-22-3p expression. Further, SIRT1 was identified to be up-regulated in TAM-resistant cells and participated in the OAS1/miR-22-3p regulatory axis via the miR-22-3p direct target. In conclusion, corylin sensitized TAM-resistant cells to TAM treatment by inhibiting OAS1 expression and modulating the OAS1/miR-22-3p/SIRT1 axis.

scholarly journals An integrative genomic analysis revealed the relevance of microRNA and gene expression for drug-resistance in human breast cancer cells

2011 ◽  
Vol 10 (1) ◽  
pp. 135 ◽  
Author(s):  
Yusuke Yamamoto ◽  
Yusuke Yoshioka ◽  
Kaho Minoura ◽  
Ryou-u Takahashi ◽  
Fumitaka Takeshita ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Genomic Analysis ◽  
Human Breast Cancer Cells ◽  
Human Breast

Down regulation of Pinkbar/pAKT and MMP2/MMP9 expression in MDA-MB-231 breast cancer cells as potential targets in cancer therapy by hAMSCs secretome

2021 ◽  
Author(s):  
Termeh Shakery ◽  
Fatemeh Safari
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
3D Cell Culture ◽  
Therapeutic Effects ◽  
Down Regulation ◽  
Egfr Signaling Pathway

Breast cancer (BC) is one of the most causes of cancer-related death among women worldwide. Cancer therapy based on stem cells was considered as a novel and promising platform. In present study, we explored the therapeutic effects of human amniotic mesenchymal stromal cells (hAMSCs) through Pinkbar (planar intestinal-and kidney-specific BAR domain protein), pAKT, and matrix metalloproteinases including MMP2, MMP9 on MDA-MB-231 breast cancer cells. To do so, we employed a co-culture system using 6 well plates transwell with a diameter of 0.4 μm pore sized. After 72h hAMSCs-treated MDA-MB-231 breast cancer cells, the expression of Epidermal growth factor receptor (EGFR), and c-Src (a key mediator in EGFR signaling pathway), Pinkbar, pAKT, MMP2, and MMP9 was analyzed by using quantitative real time PCR (qRT-PCR) and western blot methods. Based on using 2D and 3D cell culture models, the significant reduction of tumor cell growth and motility through down regulation of EGFR, c-Src, Pinkbar, pAKT, MMP2, and MMP9 in MDA-MB-231 breast cancer cells was shown. Also, the induction of cellular apoptosis also found. Our finding indicates that the hAMSCS secretome has therapeutic effects on cancer cells. To identify the details of the molecular mechanisms, more experiments will be required.

Selenadiazole derivatives antagonize hyperglycemia-induced drug resistance in breast cancer cells by activation of AMPK pathways

Metallomics ◽  
2017 ◽  
Vol 9 (5) ◽  
pp. 535-545 ◽  
Author(s):  
Jianfu Zhao ◽  
Delong Zeng ◽  
Yuedan Liu ◽  
Yi Luo ◽  
Shengbin Ji ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Breast Cancer Cells

scholarly journals ARTEMISININ MODULATING EFFECT ON HUMAN BREAST CANCER CELL LINES WITH DIFFERENT SENSITIVITY TO CYTOSTATICS

2017 ◽  
Vol 39 (1) ◽  
pp. 25-29 ◽  
Author(s):  
V F Chekhun ◽  
N Yu Lukianova ◽  
T Borikun ◽  
T Zadvornyi ◽  
A Mokhir
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Iron Homeostasis ◽  
Chemotherapeutic Agents ◽  
Fold Change ◽  
Breast Cancer Cell Lines ◽  
Cellular Iron ◽  
Mcf 7

Aim: To explore effects of Artemisinin on a series of breast cancer cells with different sensitivity to typical cytotoxic drugs (doxorubicin — Dox; cisplatin — DDP) and to investigate possible artemisinin-induced modification of the mechanisms of drug resistance. Materials and Methods: The study was performed on wild-type breast cancer MCF-7 cell line (MCF-7/S) and its two sublines MCF-7/Dox and MCF-7/DDP resistant to Dox and DDP, respectively. The cells were treated with artemisinin and iron-containing magnetic fluid. The latter was added to modulate iron levels in the cells and explore its role in artemisinin-induced effects. The MTT assay was used to monitor cell viability, whereas changes of expression of selected proteins participating in regulation of cellular iron homeostasis were estimated using immunocytochemical methods. Finally, relative expression levels of miRNA-200b, -320a, and -34a were examined by using qRT-PCR. Results: Artemisinin affects mechanisms of the resistance of breast cancer cells towards both Dox and DDP at sub-toxic doses. The former drug induces changes of expression of iron-regulating proteins via different mechanisms, including epigenetic regulation. Particularly, the disturbances in ferritin heavy chain 1, lactoferrin, hepcidin (decrease) and ferroportin (increase) expression (р ≤ 0.05) were established. The most enhanced increase of miRNA expression under artemisinin influence were found for miRNA-200b in MCF-7/DDP cells (7.1 ± 0.98 fold change), miRNA-320a in MCF-7/Dox cells (2.9 ± 0.45 fold change) and miRNA-34a (1.7 ± 0.15 fold change) in MCF-7/S cells. It was observed that the sensitivity to artemisinin can be influenced by changing iron levels in cells. Conclusions: Artemisinin can modify iron metabolism of breast cancer cells by its cytotoxic effect, but also by inducing changes in expression of iron-regulating proteins and microRNAs (miRNAs), involved in their regulation. This modification affects the mechanisms that are implicated in drug-resistance, that makes artemisinin a perspective modulator of cell sensitivity towards chemotherapeutic agents in cancer treatment.

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