scholarly journals Upregulation of SHMT2 Promotes Tumor Growth and Poor Prognosis of Breast Cancer through Activating VEGF and MAPK Signaling Pathway

2021 ◽  
Author(s):  
Shuang-Yan Xie ◽  
Dingbo Shi ◽  
Fei Lin ◽  
Xiao-Yu Cheng ◽  
Tong-chao Cheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Breast Cancer Cells ◽  
Mapk Signaling ◽  
Nucleotide Metabolism ◽  
Breast Cancers ◽  
Apoptosis Pathway

Abstract Background: Serine hydroxymethyltransferase 2 (SHMT2) is a key enzyme in Serine/glycine metabolism. SHMT2 is very important for tumor cell growth and proliferation as well as metabolism. Here, we investigated the regulatory effects of SHMT2 on breast cancers growth and identified the underlying mechanisms of functions.Methods: We detected the expression of SHMT2 in breast cancer cells and tissues by immunohistochemistry and Western blotting.We investigated the functional and molecular mechanisms by which SHMT2 downregulation or overexpression regulates the growth and apoptosis of breast cancer cells in vivo and in vitro. Results: We found SHMT2 was highly expressed in BRCA cell lines and tumor tissues. Strong SHMT2 expression showed a positive correlation with the poor prognoses of patients with breast cancers. SHMT2 knockdown by shRNA significantly inhibited cell growth and induced apoptosis in vitro, and whereas SHMT2 overexpression promoted tumor growthin in subcutaneous xenograft model. RNA-seq revealed that high expression of SHMT2 not only promoted serine metabolism, nucleotide metabolism, oxidative phosphorylation and proteasome independent degradation pathways. It also activated the cell survival signaling pathway and antagonized the apoptosis pathway. The observed molecular regulation of cell growth was accompanied by the activited of the MAPK, VEGF pathways and suppressed of the mitochondrial mediated apoptosis pathway that was mediated by the SHMT2 up-regulation. Conclusions: These results indicate that SHMT2 plays a critical role in regulating breast cancers growth and could serve as a therapeutic target for breast cancer therapy.

scholarly journals Transcriptome profiles of stem-like cells from primary breast cancers allow identification of ITGA7 as a predictive marker of chemotherapy response

2021 ◽  
Author(s):  
Noha Gwili ◽  
Stacey J. Jones ◽  
Waleed Al Amri ◽  
Ian M. Carr ◽  
Sarah Harris ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Predictive Marker ◽  
Therapy Resistance ◽  
Differentially Expressed ◽  
Molecular Profile ◽  
Chemotherapy Response ◽  
Breast Cancers

Abstract Background Breast cancer stem cells (BCSCs) are drivers of therapy-resistance, therefore are responsible for poor survival. Molecular signatures of BCSCs from primary cancers remain undefined. Here, we identify the consistent transcriptome of primary BCSCs shared across breast cancer subtypes, and we examine the clinical relevance of ITGA7, one of the genes differentially expressed in BCSCs. Methods Primary BCSCs were assessed using immunohistochemistry and fluorescently labelled using Aldefluor (n = 17). Transcriptomes of fluorescently sorted BCSCs and matched non-stem cancer cells were determined using RNA-seq (n = 6). ITGA7 expression was examined in breast cancers using immunohistochemistry (n = 305), and its functional role was tested using siRNA in breast cancer cells. Results Proportions of BCSCs varied from 0 to 9.4%. 38 genes were significantly differentially expressed in BCSCs; genes were enriched for functions in vessel morphogenesis, motility, and metabolism. ITGA7 was found to be significantly downregulated in BCSCs, and low expression significantly correlated with reduced survival in patients treated with chemotherapy, and with chemoresistance in breast cancer cells in vitro. Conclusions This study is the first to define the molecular profile of BCSCs from a range of primary breast cancers. ITGA7 acts as a predictive marker for chemotherapy response, in accordance with its downregulation in BCSCs.

PEAK1 promotes invasion and metastasis and confers drug resistance in breast cancer

2021 ◽  
Author(s):  
xingang wang ◽  
YAN ZHENG ◽  
YU WANG
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cell Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Multi Drug Resistance ◽  
Cancer Tissues

Abstract Background and AimsPseudopodium-enriched atypical kinase 1 (PEAK1) has reported to be upregulated in human malignancies and related with poor prognosis. Enhanced PEAK1 expression facilitates tumor cell survival, invasion, metastasis and chemoresistance. However, the role of PEAK1 in breast cancer is not clear. Here, we investigated the PEAK1 expression in breast cancer and analyzed its relation with clinicopathological status and chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated the role of PEAK1 on breast cancer cells in vitro and in vivo. MethodsImmunohistochemistry (IHC) was performed in 112 surgical resected breast cancer tissues. The associations between clinicopathological status, multi-drug resistance and PEAK1 expression were determined. Effect of PEAK1 overexpression or down-expression on proliferation, colony formation, invasion, migration, metastasis and Doxorubicin sensitivity in the MCF-7 cells in vitro and in vivo was detected. ResultsPEAK1 was overexpressed in breast cancer tissues and NAC -resistant breast cancer tissues. High PEAK1 expression was related with tumor size, high tumor grade, T stage, LN metastasis, recurrence, Ki-67 expression, Her-2 expression and multi-drug resistance. Targeting PEAK1 inhibited cell growth, invasion, metastasis and reversed chemoresistance to Doxorubicin in breast cancer cells in vitro and in vivo. ConclusionHigh PEAK1 expression was associated with invasion, metastasis and chemoresistance of breast cancers. Furthermore, targeting PEAK1 could inhibit cell growth and metastasis, and reverse chemoresistance in breast cancer cells, which provides an effective treatment strategies for breast cancer.

Antineoplastic Efectiveness of Silver Nanoparticles Synthesized from Onopordum Acanthium L. extract (AgNPs-OAL) toward MDA-MB231 Breast Cancer Cells

2021 ◽  
Author(s):  
Romina Delalat ◽  
Seyed Ataollah Sadat Shandiz ◽  
Bahareh Pakpour
Keyword(s):  
Breast Cancer ◽  
Silver Nanoparticles ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Annexin V ◽  
Spherical Shape ◽  
Hek293 Cells ◽  
Apoptosis Pathway ◽  
Onopordum Acanthium

Abstract The present research was done to investigate the anticancer properties of silver nanoparticles (AgNPs) fabricated using bioactive extract of Onopordum acanthium L. (AgNPs-OAL) against breast cancer cell MDA_MB231 in vitro. The determination studies of AgNPs-OAL were confirmed by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM) analysis. Interestingly, FESEM image observed the spherical shape of AgNPs-OAL with the range of 1–100 nm. As AgNP-OAL exhibited significant cytotoxicity properties on breast cancer MDA_MB231 cells with IC50 values of 66.04 μg/mL, while lowing toxicity toward normal human embryonic kidney 293 (HEK293) cells with IC50 values of 101.04 μg/mL was evaluated. Further, up-regulation of apoptotic Bax and CAD genes expressions were confirmed by quantitative real-time reverse transcription-PCR (qRT-PCR) technique results. Moreover, enhanced cell cycle population (sub-G1), annexin V/PI staining, acridine orange and ethidium bromide (AO/EB) staining, Hoescht 33258 dye, and generation of reactive oxygen species (ROS) observed in AgNP-OAL-treated MDA_MB231 cancer cells. The green-synthesized AgNP-OAL has promising anticancer efficiency that can trigger apoptosis pathway in the MDA_MB231 breast cancer cells.

scholarly journals Hyperoside Induces Breast Cancer Cells Apoptosis via ROS-Mediated NF-κB Signaling Pathway

2019 ◽  
Vol 21 (1) ◽  
pp. 131 ◽  
Author(s):  
Jinxia Qiu ◽  
Tao Zhang ◽  
Xinying Zhu ◽  
Chao Yang ◽  
Yaxing Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mouse Model ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Breast Cancer Cells ◽  
Caspase 3 ◽  
Therapeutic Potential ◽  
B Cell Lymphoma ◽  
Flavonoid Glycosides

Hyperoside (quercetin 3-o-β-d-galactopyranoside) is one of the flavonoid glycosides with anti-inflammatory, antidepressant, and anti-cancer effects. But it remains unknown whether it had effects on breast cancer. Here, different concentrations of hyperoside were used to explore its therapeutic potential in both breast cancer cells and subcutaneous homotransplant mouse model. CCK-8 and wound healing assays showed that the viability and migration capability of Michigan Cancer Foundation-7 (MCF-7) and 4T1 cells were inhibited by hyperoside, while the apoptosis of cells were increased. Real-time quantitative PCR (qRT-PCR) and western blot analysis were used to detect mRNA and the protein level, respectively, which showed decreased levels of B cell lymphoma-2 (Bcl-2) and X-linked inhibitor of apoptosis (XIAP), and increased levels of Bax and cleaved caspase-3. After exploration of the potential mechanism, we found that reactive oxygen species (ROS) production was reduced by the administration of hyperoside, which subsequently inhibited the activation of NF-κB signaling pathway. Tumor volume was significantly decreased in subcutaneous homotransplant mouse model in hyperoside-treated group, which was consistent with our study in vitro. These results indicated that hyperoside acted as an anticancer drug through ROS-related apoptosis and its mechanism included activation of the Bax–caspase-3 axis and the inhibition of the NF-κB signaling pathway.

scholarly journals Identification of hub genes associated with RNAi-induced silencing of XIAP through targeted proteomics approach in MCF7 cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mehdi Agha Gholizadeh ◽  
Fatemeh T. Shamsabadi ◽  
Ahad Yamchi ◽  
Masoud Golalipour ◽  
Gagan Deep Jhingan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Specific Antigen ◽  
Mapk Signaling ◽  
2D Electrophoresis ◽  
Mcf7 Cells ◽  
Apoptosis Pathway ◽  
Apoptosis Protein ◽  
Mcf 7

Abstract Background The X-linked inhibitor of apoptosis protein (XIAP) is the most potent caspase inhibitor of the IAP family in apoptosis pathway. This study aims to identify the molecular targets of XIAP in human breast cancer cells exposed to XIAP siRNA by proteomics screening. The expression of XIAP was reduced in MCF-7 breast cancer cells by siRNA. Cell viability and the mRNA expression level of this gene were evaluated by MTS and quantitative real-time PCR procedures, respectively. Subsequently, the XIAP protein level was visualized by Western blotting and analyzed by two-dimensional (2D) electrophoresis and LC–ESI–MS/MS. Results Following XIAP silencing, cell proliferation was reduced in XIAP siRNA transfected cells. The mRNA transcription and protein expression of XIAP were decreased in cells exposed to XIAP siRNA than si-NEG. We identified 30 proteins that were regulated by XIAP, of which 27 down-regulated and 3 up-regulated. The most down-regulated proteins belonged to the Heat Shock Proteins family. They participate in cancer related processes including apoptosis and MAPK signaling pathway. Reduced expression of HSP90B1 was associated with apoptosis induction by androgen receptor and prostate specific antigen. Suppression of XIAP resulted in the enhancement of GDIB, ENO1, and CH60 proteins expression. The network analysis of XIAP-regulated proteins identified HSPA8, HSP90AA1, ENO1, and HSPA9 as key nodes in terms of degree and betweenness centrality methods. Conclusions These results suggested that XIAP may have a number of biological functions in a diverse set of non-apoptotic signaling pathways and may provide an insight into the biomedical significance of XIAP over-expression in MCF-7 cells.

Using epigenetic reprogramming to target triple-negative breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14565-e14565
Author(s):  
D. Sharma ◽  
B. B. Knight ◽  
R. Yacoub ◽  
T. Liu ◽  
L. Taliaferro-Smith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Combined Treatment ◽  
Brdu Incorporation ◽  
Breast Cancers

e14565 Background: The outcome for patients with breast cancer has been significantly improved by the use of targeted agents. The prognosis of triple negative (TN) breast cancers, which do not express hormone receptors (ER, PR) or Her2, is poor, because of an aggressive clinical course and lack of targeted therapeutic agents. Epigenetic silencing of specific genes has been observed in breast cancer and some of these genes are more important due to available targeted therapies such as ER. Since all endocrine therapies are designed to block ER function in some way, the identification of new therapies or strategies that could sensitize TN breast cancers to existing endocrine therapy could provide a revolutionary means of treating this aggressive subtype of cancer Methods: We examined the efficacy of combined treatment of HDAC inhibitor LBH589 and DNMT inhibitor decitabine to regenerate ER and PR in TN breast cancer cells using RT-PCR and immunoblotting. Changes in growth and proliferation of TN breast cancer cells in response to LBH589 and decitabine treatment were determined by XTT, BrdU incorporation and colony formation assay. Changes in apoptotic proteins were determined by western blotting. Athymic nude mice were used to establish pre-clinical models for TN breast cancer cells and effectiveness of combined treatment of LBH589 and decitabine was determined. Tumors biopsies were analyzed for ER and PR re-expression by western blot analysis and immunohistochemistry at the end of the treatment. Results: Combined treatment of LBH589 and decitabine resulted in re-expression of ER and PR in TN breast cancers in vitro and in vivo. Although re-expression of ER and PR were noted following LBH589 treatment alone, re-expression was more robust with the combination. TN breast cancer cells showing re-expressed ER can be targeted with tamoxifen. Tamoxifen inhibits growth of TN breast cancer cells re- expressing ER by triggering apoptosis. Conclusions: The importance of epigenetic events such as DNA methylation and HDAC inhibition in tumor progression is becoming increasingly evident. A trial evaluating the ability of LBH589 and decitabine to re- express ER, which can then be targeted by tamoxifen, is planned in patients with metastatic TN breast cancer. No significant financial relationships to disclose.

scholarly journals Estrogen deprivation triggers an immunosuppressive phenotype in breast cancer cells

2019 ◽  
Author(s):  
Daniela Hühn ◽  
Pablo Martí-Rodrigo ◽  
Silvana Mouron ◽  
Catherine S. Hansel ◽  
Kirsten Tschapalda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Mcf7 Cells ◽  
Estrogen Deprivation ◽  
Er Positive

ABSTRACTEstrogen receptor (ER)-positive breast tumors are routinely treated with estrogen-depriving therapies. Despite their effectiveness, patients often progress into a more aggressive form of the disease. Through a chemical screen oriented to identify chemicals capable of inducing the expression of the immune-checkpoint ligand PD-L1, we found antiestrogens as hits. Subsequent validations confirmed that estrogen deprivation or ERα depletion induces PD-L1 expression in ER-positive breast cancer cells, both in vitro and in vivo. Likewise, PD-L1 expression is increased in metastasis arising from breast cancer patients receiving adjuvant hormonal therapy for their local disease. Transcriptome analyses indicate that estrogen deprivation triggers a broad immunosuppressive program, not restricted to PD-L1. Accordingly, estrogen deprived MCF7 cells are resistant to T-cell mediated cell killing, in a manner that can be reverted by estradiol. Our study reveals that while antiestrogen therapies effectively limit tumor growth in ER-positive breast cancers, they also trigger a transcriptional program that favors immune evasion.

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