Inhibitory effects of iron depletion plus eribulin on the breast cancer microenvironment

Abstract Background Iron is required for the proliferation of cancer cells, and its depletion suppresses tumor growth. Eribulin mesylate (eribulin), a non-taxane microtubule inhibitor, disrupts the tumor microenvironment via vascular remodeling and obstruction of the epithelial-mesenchymal transition (EMT). Herein, we investigated the effects of the iron chelator on tumor-related properties of breast cancer cells and the effects of iron chelator plus eribulin on tumor growth in vivo. Methods Two triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and BT-549, and one hormone-receptor positive breast cancer cell line, MCF-7, were used in our study. Cell proliferation, cell migration, cell cycle position, and gene expression were analyzed via MTT assays, wound-healing assays, flow cytometry, and quantitative real-time-polymerase chain reaction, respectively. For the in vivo experiments, mice with breast cancer xenografts were treated with the inhibitors, alone or together, and tumor volume was determined. Results Iron chelator inhibited breast cancer cell proliferation and decreased the proportion of S-phase cells. Conversely, it induced hypoxia, angiogenesis, EMT, and immune checkpoints, as determined by quantifying the expression of marker mRNAs in MDA-MB-231 and MCF-7 cells. Eribulin suppressed the expression of the hypoxia and EMT related marker mRNAs in the presence of iron chelator. Iron chelator plus eribulin inhibited tumor growth in vivo to a greater extent than did either inhibitor alone. Conclusions Although iron chelator induces oncogenic events (hypoxia, angiogenesis, EMT, and immune checkpoints), it may be an effective treatment for breast cancer when administered in combination with eribulin.

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Inhibitory effects of iron depletion plus eribulin on the breast cancer microenvironment

10.21203/rs.3.rs-16369/v5 ◽

2020 ◽

Author(s):

Wataru Goto ◽

Shinichiro Kashiwagi ◽

Yuka Asano ◽

Koji Takada ◽

Tamami Morisaki ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Tumor Growth ◽

Cancer Cells ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Iron Chelator ◽

Immune Checkpoints ◽

Mcf 7

Abstract Background: Iron is required for the proliferation of cancer cells, and its depletion suppresses tumor growth. Eribulin mesylate (eribulin), a non-taxane microtubule inhibitor, disrupts the tumor microenvironment via vascular remodeling and obstruction of the epithelial-mesenchymal transition (EMT). Herein, we investigated the effects of the iron chelator on tumor-related properties of breast cancer cells and the effects of iron chelator plus eribulin on tumor growth in vivo.Methods: Two triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and BT-549, and one hormone-receptor positive breast cancer cell line, MCF-7, were used in our study. Cell proliferation, cell migration, cell cycle position, and gene expression were analyzed via MTT assays, wound-healing assays, flow cytometry, and quantitative real-time-polymerase chain reaction, respectively. For the in vivo experiments, mice with breast cancer xenografts were treated with the inhibitors, alone or together, and tumor volume was determined.Results: Iron chelator inhibited breast cancer cell proliferation and decreased the proportion of S-phase cells. Conversely, it induced hypoxia, angiogenesis, EMT, and immune checkpoints, as determined by quantifying the expression of marker mRNAs in MDA-MB-231 and MCF-7 cells. Eribulin suppressed the expression of the hypoxia and EMT related marker mRNAs in the presence of iron chelator. Iron chelator plus eribulin inhibited tumor growth in vivo to a greater extent than did either inhibitor alone.Conclusions: Although iron chelator induces oncogenic events (hypoxia, angiogenesis, EMT, and immune checkpoints), it may be an effective treatment for breast cancer when administered in combination with eribulin.

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Inhibitory effects of iron depletion plus eribulin on the breast cancer microenvironment

10.21203/rs.3.rs-16369/v4 ◽

2020 ◽

Author(s):

Wataru Goto ◽

Shinichiro Kashiwagi ◽

Yuka Asano ◽

Koji Takada ◽

Tamami Morisaki ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Tumor Growth ◽

Cancer Cells ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Iron Chelator ◽

Immune Checkpoints ◽

Mcf 7

Abstract Background: Iron is required for the proliferation of cancer cells, and its depletion suppresses tumor growth. Eribulin mesylate (eribulin), a non-taxane microtubule inhibitor, disrupts the tumor microenvironment via vascular remodeling and obstruction of the epithelial-mesenchymal transition (EMT). Herein, we investigated the effects of the iron chelator on tumor-related properties of breast cancer cells and the effects of iron chelator plus eribulin on tumor growth in vivo.Methods: Two triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and BT-549, and one hormone-receptor positive breast cancer cell line, MCF-7, were used in our study. Cell proliferation, cell migration, cell cycle position, and gene expression were analyzed via MTT assays, wound-healing assays, flow cytometry, and quantitative real-time-polymerase chain reaction, respectively. For the in vivo experiments, mice with breast cancer xenografts were treated with the inhibitors, alone or together, and tumor volume was determined.Results: Iron chelator inhibited breast cancer cell proliferation and decreased the proportion of S-phase cells. Conversely, it induced hypoxia, angiogenesis, EMT, and immune checkpoints, as determined by quantifying the expression of marker mRNAs in MDA-MB-231 and MCF-7 cells. Eribulin suppressed the expression of the hypoxia and EMT related marker mRNAs in the presence of iron chelator. Iron chelator plus eribulin inhibited tumor growth in vivo to a greater extent than did either inhibitor alone.Conclusions: Although iron chelator induces oncogenic events (hypoxia, angiogenesis, EMT, and immune checkpoints), it may be an effective treatment for breast cancer when administered in combination with eribulin.

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Inhibitory effects of iron depletion plus eribulin on the breast cancer microenvironment

10.21203/rs.3.rs-16369/v2 ◽

2020 ◽

Author(s):

Wataru Goto ◽

Shinichiro Kashiwagi ◽

Yuka Asano ◽

Koji Takada ◽

Tamami Morisaki ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Tumor Growth ◽

Cancer Cells ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Immune Checkpoints ◽

Mesenchymal Transition ◽

Mcf 7

Abstract Background: Iron is required for the proliferation of cancer cells, and its depletion suppresses tumor growth. Eribulin mesylate (eribulin), a non-taxane microtubule inhibitor, disrupts the tumor microenvironment via vascular remodeling and obstruction of the epithelial-mesenchymal transition (EMT). Herein, we investigated the effects of the iron chelator deferoxamine (DFO) on tumor-related properties of breast cancer cells and the effects of DFO plus eribulin on tumor growth in vivo.Methods: Two triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and BT-549, and one hormone-receptor positive breast cancer cell line, MCF-7, were used in our study. Cell proliferation, cell migration, cell cycle position, and gene expression were analyzed via MTT assays, wound-healing assays, flow cytometry, and quantitative real-time-polymerase chain reaction, respectively. For the in vivo experiments, mice with breast cancer xenografts were treated with the inhibitors, alone or together, and tumor volume was determined.Results: DFO inhibited breast cancer cell proliferation and migration and decreased the proportion of S-phase cells. Conversely, it induced hypoxia, angiogenesis, EMT, and immune checkpoints, as determined by quantifying the expression of marker mRNAs in MDA-MB-231 and MCF-7 cells. Eribulin suppressed the expression of the hypoxia and EMT related marker mRNAs in the presence of DFO. DFO plus eribulin inhibited tumor growth in vivo to a greater extent than did either inhibitor alone.Conclusions: Although DFO induces oncogenic events (hypoxia, angiogenesis, EMT, and immune checkpoints), it may be an effective treatment for breast cancer when administered in combination with eribulin.

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Inhibition of MCF-7 breast cancer cell proliferation and in vivo steroid sulphatase activity by 2-methoxyoestradiol-bis-sulphamate

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/s0960-0760(03)00049-9 ◽

2003 ◽

Vol 84 (2-3) ◽

pp. 351-358 ◽

Cited By ~ 34

Author(s):

Bindumalini Raobaikady ◽

Atul Purohit ◽

Surinder K. Chander ◽

L.W.Lawrence Woo ◽

Mathew P. Leese ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Cell Proliferation ◽

Breast Cancer Cell Proliferation ◽

Steroid Sulphatase ◽

Mcf 7

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Knockdown of Efp by DNA-modified small interfering RNA inhibits breast cancer cell proliferation and in vivo tumor growth

Cancer Gene Therapy ◽

10.1038/cgt.2010.19 ◽

2010 ◽

Vol 17 (9) ◽

pp. 624-632 ◽

Cited By ~ 24

Author(s):

K Ueyama ◽

K Ikeda ◽

W Sato ◽

N Nakasato ◽

K Horie-Inoue ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Tumor Growth ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Small Interfering Rna ◽

Cancer Cell Proliferation ◽

Breast Cancer Cell Proliferation ◽

Interfering Rna

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Inhibitory effects of iron depletion plus eribulin on the breast cancer microenvironment

10.21203/rs.3.rs-16369/v1 ◽

2020 ◽

Author(s):

Wataru Goto ◽

Shinichiro Kashiwagi ◽

Yuka Asano ◽

Koji Takada ◽

Tamami Morisaki ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Tumor Growth ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Immune Checkpoints ◽

Microtubule Inhibitor ◽

Eribulin Mesylate ◽

Mesenchymal Transition

Abstract Background Iron is required for the proliferation of cancer cells, and its depletion suppresses tumor growth. Eribulin mesylate (eribulin), a non-taxane microtubule inhibitor, disrupts the tumor microenvironment via vascular remodeling and obstruction of the epithelial-mesenchymal transition (EMT). Herein, we investigated the effects of the iron chelator deferoxamine (DFO) on tumor-related properties of breast cancer cells and the effects of DFO plus eribulin on tumor growth in vivo . Methods A triple-negative breast cancer (TNBC) cell line (MDA-MB-231) was used in our study. Cell proliferation, cell migration, cell cycle position, and gene expression were analyzed via MTT assays, wound-healing assays, flow cytometry, and quantitative real-time-polymerase chain reaction, respectively. For the in vivo experiments, mice with MDA-MB-231 xenografts were treated with the inhibitors, alone or together, and tumor volume was determined. Results DFO inhibited breast cancer cell proliferation and migration and decreased the proportion of S-phase cells. Conversely, it induced hypoxia, angiogenesis, EMT, and immune checkpoints, as determined by quantifying the expression of marker mRNAs. Eribulin suppressed the expression of the EMT marker mRNAs in the presence of DFO. DFO plus eribulin inhibited tumor growth in vivo to a greater extent than did either inhibitor alone. Conclusions Although DFO induces oncogenic events (hypoxia, angiogenesis, EMT, and immune checkpoints), it may be an effective treatment for breast cancer when administered in combination with eribulin.

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Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy

Endocrine Related Cancer ◽

10.1530/erc-15-0063 ◽

2015 ◽

Vol 22 (5) ◽

pp. 831-840 ◽

Cited By ~ 31

Author(s):

Erik Hedrick ◽

Syng-Ook Lee ◽

Ravi Doddapaneni ◽

Mandip Singh ◽

Stephen Safe

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Cell Lines ◽

Nuclear Receptor ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Breast Cancer Cells ◽

Induced Apoptosis ◽

Mcf 7

The orphan nuclear receptor 4A1 (NR4A1) is overexpressed in mammary tumors and breast cancer cell lines. The functional activity of this receptor was investigated by RNA interference with oligonucleotides targeted to NR4A1 (siNR4A1) and by treatment with NR4A1 antagonists. Breast cancer cells were treated with NR4A1 antagonists or transfected with siNR4A. Effects on cell proliferation and apoptosis as well as specific genes associated with these responses were investigated in MCF-7, SKBR3, and MDA-MB-231 cells, and in athymic nude mice bearing MDA-MB-231 cells as xenografts. Transfection of MCF-7, MDA-MB-231, and SKBR3 breast cancer cells with siNR4A1 decreased cell proliferation and induced apoptosis in these cell lines. Transfection of breast cancer cells with siNR4A1 also decreased expression of Sp-regulated genes includingsurvivin,bcl-2, and epidermal growth factor receptor, inhibited mTOR signaling in MCF-7 cells that express WT p53, and activated oxidative and endoplasmic reticulum stress through downregulation of thioredoxin domain-containing 5 and isocitrate dehydrogenase 1. 1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) are NR4A1 ligands that act as NR4A1 antagonists. Treatment with selected analogs also inhibited breast cancer cell and tumor growth and induced apoptosis. The effects of C-DIM/NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. Results with siNR4A1 or C-DIMs/NR4A1 antagonists in breast cancer cells and tumors were similar to those previously reported in pancreatic, lung, and colon cancer cells. They demonstrate the potential clinical applications of NR4A1 antagonists in patients with tumors that overexpress this receptor.

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AKR1B10 promotes breast cancer cell proliferation and migration via the PI3K/AKT/NF-κB signaling pathway

Cell & Bioscience ◽

10.1186/s13578-021-00677-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jiayao Qu ◽

Jia Li ◽

Yaming Zhang ◽

Rongzhang He ◽

Xiangting Liu ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Breast Cancer Cells ◽

Migration And Invasion ◽

Breast Cancer Cell Lines ◽

Related Proteins ◽

Mcf 7

Abstract Background Aberrant expression of Aldo-Keto reductase family 1 member B10 (AKR1B10) was associated with tumor size and metastasis of breast cancer in our published preliminary studies. However, little is known about the detailed function and underlying molecular mechanism of AKR1B10 in the pathological process of breast cancer. Methods The relationship between elevated AKR1B10 expression and the overall survival and disease-free survival of breast cancer patients was analyzed by Kaplan–Meier Plotter database. Breast cancer cell lines overexpressing AKR1B10 (MCF-7/AKR1B10) and breast cancer cell lines with knockdown of AKR1B10 (BT-20/shAKR1B10) were constructed to analyze the impact of AKR1B10 expression on cell proliferation and migration of breast cancer. The expression levels of AKR1B10 were detected and compared in the breast cancer cell lines and tissues by RT-qPCR, western blot and immunohistochemistry. The proliferation of breast cancer cells was monitored by CCK8 cell proliferation assay, and the migration and invasion of breast cancer cells was observed by cell scratch test and transwell assay. The proliferation- and EMT-related proteins including cyclinD1, c-myc, Survivin, Twist, SNAI1, SLUG, ZEB1, E-cadherin, PI3K, p-PI3K, AKT, p-AKT, IKBα, p-IKBα, NF-κB p65, p-NF-κB p65 were detected by western blot in breast cancer cells. MCF-7/AKR1B10 cells were treated with LY294002, a PI3K inhibitor, to consider the impact of AKR1B10 overexpression on the PI3K/AKT/NF-κB signal cascade and the presence of NF-κB p65 in nuclear. In vivo tumor xenograft experiments were used to observe the role of AKR1B10 in breast cancer growth in mice. Results AKR1B10 expression was significantly greater in breast cancer tissue compared to paired non-cancerous tissue. The expression of AKR1B10 positively correlated with lymph node metastasis, tumor size, Ki67 expression, and p53 expression, but inversely correlated with overall and disease-free survival rates. Gene Ontology analysis showed that AKR1B10 activity contributes to cell proliferation. Overexpression of AKR1B10 facilitated the proliferation of MCF-7 cells, and induced the migration and invasion of MCF-7 cells in vitro in association with induction of epithelial-mesenchymal transition (EMT). Conversely, knockdown of AKR1B10 inhibited these effects in BT-20 cells. Mechanistically, AKR1B10 activated PI3K, AKT, and NF-κB p65, and induced nuclear translocation of NF-κB p65, and expression of proliferation-related proteins including c-myc, cyclinD1, Survivin, and EMT-related proteins including ZEB1, SLUG, Twist, but downregulated E-cadherin expression in MCF-7 cells. AKR1B10 silencing reduced the phosphorylation of PI3K, AKT, and NF-κB p65, the nuclear translocation of NF-κB p65, and the expression of proliferation- and migration-related proteins in BT-20 cells. LY294002, a PI3K inhibitor, attenuated the phosphorylation of PI3K, AKT, and NF-κB p65, and the nuclear translocation of NF-κB p65. In vivo tumor xenograft experiments confirmed that AKR1B10 promoted breast cancer growth in mice. Conclusions AKR1B10 promotes the proliferation, migration and invasion of breast cancer cells via the PI3K/AKT/NF-κB signaling pathway and represents a novel prognostic indicator as well as a potential therapeutic target in breast cancer.

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