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

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.

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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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Drug-resistant cancer cell-derived exosomal EphA2 promotes breast cancer metastasis via the EphA2-Ephrin A1 reverse signaling

10.21203/rs.3.rs-103652/v1 ◽

2020 ◽

Author(s):

Zicong Gao ◽

Xingxing Han ◽

Yuying Zhu ◽

He Zhang ◽

Ran Tian ◽

...

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Resistant Cell ◽

Migration And Invasion ◽

Drug Resistant ◽

Resistant Cells

Abstract Background: The failure of chemotherapy is accompanied by the emergence of drug resistance and tumor relapse. Tumor metastasis induced by drug resistance is a major challenge in successful cancer treatment. Nevertheless, the mechanisms underlying the pro-invasive and metastatic ability of drug resistance remain elusive. Exosome-mediated intercellular communications between cancer cells and stromal cells in tumor microenvironment are required for cancer initiation and progression. Recent reports have shown that communications between cancer cells also promote tumor aggression. However, little attention has been regarded on this aspect. In this study, we aimed to investigate the mechanisms of exosomes derived from drug-resistant cells in regulating the invasion and metastasis of sensitive breast cancer cells.Methods: Exosomes isolated from drug-resistant breast cancer cells and their parental cells were used to treat breast cancer cells, and then the migration and invasion abilities were examined. The tandem mass tag (TMT)-based quantitative proteomic method was carried out to identify key molecules that regulate cancer aggressiveness. Lentivirus-mediated shRNAs, overexpression, point mutation, truncation mutation, Western blotting, tumor xenograft mice models, and in vivo breast cancer metastatic models were used to investigate the functional role of EphA2 on the invasion and metastatic potential of breast cancer cells.Results: We demonstrated that drug-resistant cell-derived exosomes promoted the migration and invasion of sensitive breast cancer cells. Quantitative proteomic analysis showed that EphA2 was rich in exosomes from drug-resistant cells. Exosomal EphA2 conferred the invasive/metastatic phenotype transfer from drug-resistant cells to sensitive cells. In addition, we provided considerable evidence that exosomal EphA2 activated ERK1/2 signaling through the ligand Ephrin A1-dependent reverse pathway rather than the forward pathway, thereby promoting breast cancer progression. Conclusions: Our findings indicate the key functional role of exosomal EphA2 in the transmission of aggressive phenotype between cancer cells that do not rely on direct cell–cell contact. Our study also suggests that the increase of EphA2 in drug-resistant cell-derived exosomes may be an important mechanism of chemotherapy/drug resistance-induced breast cancer progression.

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

10.21203/rs.3.rs-136924/v1 ◽

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.

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Faculty Opinions recommendation of LEM4 confers tamoxifen resistance to breast cancer cells by activating cyclin D-CDK4/6-Rb and ERα pathway.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.734203067.793551626 ◽

2018 ◽

Author(s):

Wafik El-Deiry ◽

Shuai Zhao

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tamoxifen Resistance ◽

Cyclin D

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CD63 + Cancer‐Associated Fibroblasts Confer Tamoxifen Resistance to Breast Cancer Cells through Exosomal miR‐22

Advanced Science ◽

10.1002/advs.202002518 ◽

2020 ◽

Vol 7 (21) ◽

pp. 2002518

Author(s):

Yuan Gao ◽

Xiaoju Li ◽

Cheng Zeng ◽

Chenlin Liu ◽

Qiang Hao ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tamoxifen Resistance ◽

Cancer Associated Fibroblasts

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Double Methotrexate-Modified Neuropeptide Y Analogues Express Increased Toxicity and Overcome Drug Resistance in Breast Cancer Cells

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.6b00043 ◽

2016 ◽

Vol 59 (7) ◽

pp. 3409-3417 ◽

Cited By ~ 17

Author(s):

David Böhme ◽

Jan Krieghoff ◽

Annette G. Beck-Sickinger

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Neuropeptide Y ◽

Cancer Cells ◽

Breast Cancer Cells

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

Molecular Cancer ◽

10.1186/1476-4598-10-135 ◽

2011 ◽

Vol 10 (1) ◽

pp. 135 ◽

Cited By ~ 73

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

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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

Cells Tissues Organs ◽

10.1159/000520370 ◽

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.

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