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UBE2T mediates the stemness properties of breast cancer cells through the mTOR signaling pathway
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作者 JIAWEI YIN YONGSHENG WANG +1 位作者 GUANGWEI WEI MINGXIN WEN 《BIOCELL》 SCIE 2024年第6期959-970,共12页
Objectives:This study aimed to reveal the role and possible mechanism of the ubiquitin-conjugating enzyme 2T(UBE2T)in the biological activities of breast cancer stem cells(BCSCs).Methods:The specific protein and gene ... Objectives:This study aimed to reveal the role and possible mechanism of the ubiquitin-conjugating enzyme 2T(UBE2T)in the biological activities of breast cancer stem cells(BCSCs).Methods:The specific protein and gene expression were quantified by Western blotting and quantitative real-time polymerase chain reaction,the proportion of BCSCs was examined by flow cytometry,and the self-renewal and proliferation of BCSCs were verified by serial sphere formation and soft agar.Results:Increasing expression of UBE2T was drastically found in breast cancer than that in adjacent tissues.Furthermore,UBE2T overexpression significantly increased the proportion of BCSCs in breast cancer cells and promoted their self-renewal and proliferation.Silent UBE2T exhibited the opposite functions.UBE2T increased the levels of the mammalian target of rapamycin and the phosphorylated mammalian target of rapamycin.Mammalian target of rapamycin(mTOR)inhibitor rapamycin inhibited the function of UBE2T in BCSCs.Conclusion:UBE2T plays a role in BCSCs through mTOR pathway and may suggest a novel therapeutic strategy for breast cancer. 展开更多
关键词 UBE2T breast cancer breast cancer stem cell MTOR
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Analysis of Differential Gene Expression and Core Canonical Pathways Involved in the Epithelial to Mesenchymal Transition of Triple Negative Breast Cancer Cells by Ingenuity Pathway Analysis
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作者 Elizabeth Cagle Brent Lake +10 位作者 Anasua Banerjee Jazmine Cuffee Narendra Banerjee Darla Gilmartin Makaiyah Liverman Shennel Brown Erik Armstrong Santanu Bhattacharya Somiranjan Ghosh Tanmoy Mandal Hirendra Banerjee 《Computational Molecular Bioscience》 2023年第2期21-34,共14页
Triple Negative Breast Cancer (TNBC) is a malignant form of cancer with very high mortality and morbidity. Epithelial to Mesenchymal Transition (EMT) is the most common pathophysiological change observed in cancer cel... Triple Negative Breast Cancer (TNBC) is a malignant form of cancer with very high mortality and morbidity. Epithelial to Mesenchymal Transition (EMT) is the most common pathophysiological change observed in cancer cells of epithelial origin that promotes metastasis, drug resistance and cancer stem cell formation. Since the information regarding differential gene expression in TNBC cells and cell signaling events leading to EMT is limited, this investigation was done by comparing transcriptomic data generated by RNA isolation and sequencing of a EMT model TNBC cell line in comparison to regular TNBC cells. RNA sequencing and Ingenuity Pathway Software Analysis (IPA) of the transcriptomic data revealed several upregulated and downregulated gene expressions along with novel core canonical pathways including Sirtuin signaling, Oxidative Phosphorylation and Mitochondrial dysfunction events involved in EMT changes of the TNBC cells. 展开更多
关键词 triple negative breast cancer Epithelial to Mesenchymal Transition Core Canonical Pathways
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Role of cancer stem cell ecosystem on breast cancer metastasis and related mouse models
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作者 Xilei Peng Haonan Dong +1 位作者 Lixing Zhang Suling Liu 《Zoological Research》 SCIE CSCD 2024年第3期506-517,共12页
Breast cancer metastasis is responsible for most breast cancer-related deaths and is influenced by many factors within the tumor ecosystem,including tumor cells and microenvironment.Breast cancer stem cells(BCSCs)cons... Breast cancer metastasis is responsible for most breast cancer-related deaths and is influenced by many factors within the tumor ecosystem,including tumor cells and microenvironment.Breast cancer stem cells(BCSCs)constitute a small population of cancer cells with unique characteristics,including their capacity for self-renewal and differentiation.Studies have shown that BCSCs not only drive tumorigenesis but also play a crucial role in promoting metastasis in breast cancer.The tumor microenvironment(TME),composed of stromal cells,immune cells,blood vessel cells,fibroblasts,and microbes in proximity to cancer cells,is increasingly recognized for its crosstalk with BCSCs and role in BCSC survival,growth,and dissemination,thereby influencing metastatic ability.Hence,a thorough understanding of BCSCs and the TME is critical for unraveling the mechanisms underlying breast cancer metastasis.In this review,we summarize current knowledge on the roles of BCSCs and the TME in breast cancer metastasis,as well as the underlying regulatory mechanisms.Furthermore,we provide an overview of relevant mouse models used to study breast cancer metastasis,as well as treatment strategies and clinical trials addressing BCSC-TME interactions during metastasis.Overall,this study provides valuable insights for the development of effective therapeutic strategies to reduce breast cancer metastasis. 展开更多
关键词 breast cancer METASTASIS cancer stem cell ECOSYstem Tumor microenvironment Mouse model
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Research Progress of Breast Cancer Stem Cell Stemness and Breast Cancer Recurrence
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作者 Huifang Zeng Guanming Lu 《Journal of Biosciences and Medicines》 2024年第8期281-294,共14页
Currently, breast cancer is the most common malignant tumour in Chinese women with a high incidence rate, and recurrence and metastasis are the main reasons affecting survival. Breast Cancer Stem Cells (BCSCs) are ste... Currently, breast cancer is the most common malignant tumour in Chinese women with a high incidence rate, and recurrence and metastasis are the main reasons affecting survival. Breast Cancer Stem Cells (BCSCs) are stem cells capable of continuous regeneration in vivo with strong self-renewal ability and multidirectional differentiation potential, which are highly tumourigenic and insensitive to radiotherapy and chemotherapy, and are highly susceptible to breast cancer recurrence. Therefore, exploring the stemness of BCSCs and their mechanism associated with recurrence is important for developing new therapeutic strategies, improving therapeutic efficacy, and improving patient prognosis. 展开更多
关键词 breast cancer stem cells stemNESS RECURRENCE Tumour Microenvironment Drug Resistance
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Cancer stem-like cells directly participate in vasculogenic mimicry channels in triple-negative breast cancer 被引量:8
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作者 Huizhi Sun Nan Yao +6 位作者 Siqi Cheng Linqi Li Shiqi Liu Zhao Yang Guanjie Shang Danfang Zhang Zhi Yao 《Cancer Biology & Medicine》 SCIE CAS CSCD 2019年第2期299-311,共13页
Objective: Vasculogenic mimicry(VM) channels that are lined by tumor cells are a functional blood supply in malignant tumors.However, the role of VM-initiating cells remains poorly understood. Cancer stem-like cells(C... Objective: Vasculogenic mimicry(VM) channels that are lined by tumor cells are a functional blood supply in malignant tumors.However, the role of VM-initiating cells remains poorly understood. Cancer stem-like cells(CSCs) are positively correlated with VM. In this study, triple-negative breast cancer(TNBC) enriched with CSCs was used to investigate the relationship between VM and CSCs.Methods: The expression of several CSC markers was detected by immunohistochemistry in 100 human breast cancer samples.The clinical significance of CSC markers and the relationship between VM, CSCs, breast cancer subtypes, and VM-associated proteins were analyzed. CD133+ and ALDH+ human and mouse TNBC cells were isolated by FACS to examine the ability of VM formation and the spatial relationship between VM and CSCs.Results: CSCs were associated with TNBC subtype and VM in human invasive breast cancer. CSCs in TNBC MDA-MB-231 cells formed more VM channels and expressed more molecules promoting VM than the non-TNBC MCF-7 cells in vitro. MDA-MB-231 cells that encircled VM channels on Matrigel expressed CD133. Moreover, CSCs were located near VM channels in the 3D reconstructed blood supply system in human TNBC grafts. The CD133+ and ALDH+ cells isolated from TA2 mouse breast cancer formed more VM channels in vivo.Conclusions: CSCs line VM channels directly. Additionally, CSCs provide more VM-related molecules to synergize VM formation. The signaling pathways that control CSC differentiation may also be potential treatment targets for TNBC. 展开更多
关键词 Vasculogenic MIMICRY triple-negative breast cancer cancer stem-like cells ALDH1 CD 133
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Senescent mesenchymal stem/stromal cells in pre-metastatic bone marrow of untreated advanced breast cancer patients
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作者 FRANCISCO RAÚL BORZONE MARÍA BELÉN GIORELLO +6 位作者 LEANDRO MARCELO MARTINEZ MARÍA CECILIA SANMARTIN LEONARDO FELDMAN FEDERICO DIMASE EMILIO BATAGELJ GUSTAVO YANNARELLI NORMA ALEJANDRA CHASSEING 《Oncology Research》 SCIE 2023年第3期361-374,共14页
Breast cancer is the predominant form of carcinoma among women worldwide,with 70%of advanced patients developing bone metastases,with a high mortality rate.In this sense,the bone marrow(BM)mesenchymal stem/stromal cel... Breast cancer is the predominant form of carcinoma among women worldwide,with 70%of advanced patients developing bone metastases,with a high mortality rate.In this sense,the bone marrow(BM)mesenchymal stem/stromal cells(MSCs)are critical for BM/bone homeostasis,and failures in their functionality,transform the BM into a premetastatic niche(PMN).We previously found that BM-MSCs from advanced breast cancer patients(BCPs,infiltrative ductal carcinoma,stage III-B)have an abnormal profile.This work aims to study some of the metabolic and molecular mechanisms underlying MSCs shift from a normal to an abnormal profile in this group of patients.A comparative analysis was undertaken,which included self-renewal capacity,morphology,proliferation capacity,cell cycle,reactive oxygen species(ROS)levels,and senescence-associatedβ‑galactosidase(SA‑β‑gal)staining of BMderived MSCs isolated from 14 BCPs and 9 healthy volunteers(HVs).Additionally,the expression and activity of the telomerase subunit TERT,as well as telomere length,were measured.Expression levels of pluripotency,osteogenic,and osteoclastogenic genes(OCT-4,SOX-2,M-CAM,RUNX-2,BMP-2,CCL-2,M-CSF,and IL-6)were also determined.The results showed that MSCs from BCPs had reduced,self-renewal and proliferation capacity.These cells also exhibited inhibited cell cycle progression and phenotypic changes,such as an enlarged and flattened appearance.Additionally,there was an increase in ROS and senescence levels and a decrease in the functional capacity of TERT to preserve telomere length.We also found an increase in pro-inflammatory/pro-osteoclastogenic gene expression and a decrease in pluripotency gene expression.We conclude that these changes could be responsible for the abnormal functional profile that MSCs show in this group of patients. 展开更多
关键词 Mesenchymal stem/stromal cells Senescence breast cancer Bone marrow Pre-metastatic niche Bone metastasis
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Role of adipose-derived stem cells in breast cancer
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作者 Wanwen Dang Junhao Wu +2 位作者 Guanhuier Wang Yonghuan Zhen Yang An 《Chinese Journal of Plastic and Reconstructive Surgery》 2023年第2期73-79,共7页
The clinical use of fat grafts for breast reconstruction post-mastectomy or radiotherapy has the disadvantages of limited retention and survival rates.To solve this problem,adipose-derived stem cells(ADSCs)have been s... The clinical use of fat grafts for breast reconstruction post-mastectomy or radiotherapy has the disadvantages of limited retention and survival rates.To solve this problem,adipose-derived stem cells(ADSCs)have been suggested as an alternative cell source for breast reconstruction,because they are simple to access,have low immunogenicity,and support the survival of mature adipose grafts.However,despite their outstanding properties,the use of ADSCs in patients with breast cancer is controversial,and the oncological safety of this method has been questioned.The biological effects of ADSCs on breast cancer are complex,and clinical research on ADSC-assisted fat grafting is limited.Here,we review the current experimental findings on the effects of ADSCs on breast cancer,mainly focusing on the role of ADSCs in breast cancer proliferation and growth processes,such as epithelial-mesenchymal transition(EMT)and angiogenesis.We also discuss the safety of ADSCs in clinical breast reconstruction. 展开更多
关键词 Adipose-derived stem cells breast cancer breast reconstruction Cell-assisted lipotransfer
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Systemic treatment strategies for triple-negative breast cancer 被引量:19
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作者 Budhi Singh Yadav Suresh C Sharma +1 位作者 Priyanka Chanana Swaty Jhamb 《World Journal of Clinical Oncology》 CAS 2014年第2期125-133,共9页
Triple-negative breast cancer(TNBC) is defined by the lack of immunohistochemical expression of the estrogen and progesterone receptors and human epidermal growth factor receptor 2(EGFR2). Most TNBC has a basal-like m... Triple-negative breast cancer(TNBC) is defined by the lack of immunohistochemical expression of the estrogen and progesterone receptors and human epidermal growth factor receptor 2(EGFR2). Most TNBC has a basal-like molecular phenotype by gene expression profiling and shares clinical and pathological features with hereditary BRCA1 related breast cancers. This review evaluates the activity of available chemotherapy and targeted agents in TNBC. A systematic review of PubM ed and conference databases was carried out to identify randomised clinical trials reporting outcomes in women with TNBC treated with chemotherapy and targeted agents. Our review identified TNBC studies of chemotherapy and targeted agents with different mechanisms of action, including induction of synthetic lethality and inhibition of angiogenesis, growth and survival pathways. TNBC is sensitive to taxanes and anthracyclins. Platinum agents are effective in TNBC patients with BRCA1 mutation, either alone or in combination with poly adenosine diphosphate polymerase 1 inhibitors. Combinations of ixabepilone and capecitabine have added to progression-free survival(PFS) without survival benefit in metastatic TNBC. Antiangiogenic agents, tyrosine kinase inhibitors and EGFR inhibitorsin combination with chemotherapy produced only modest gains in PFS and had little impact on survival. TNBC subgroups respond differentially to specific targeted agents. In future, the treatment needs to be tailored for a specific patient, depending on the molecular characteristics of their malignancy. TNBC being a chemosensitive entity, combination with targeted agents have not produced substantial improvements in outcomes. Appropriate patient selection with rationale combinations of targeted agents is needed for success. 展开更多
关键词 breast cancer triple negative BASAL like BRCA1 Poly(ADP-ribose)polymerase 1 TARGETED therapy Chemotherapy
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HIF-2α regulates CD44 to promote cancer stem cell activation in triple-negative breast cancer via PI3K/AKT/mTOR signaling 被引量:12
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作者 Jie Bai Wei-Bin Chen +4 位作者 Xiao-Yu Zhang Xiao-Ning Kang Li-Jun Jin Hui Zhang Zun-Yi Wang 《World Journal of Stem Cells》 SCIE 2020年第1期87-99,共13页
BACKGROUND Breast cancer is a common malignant tumor that seriously threatens women’s health.Breast cancer stem cell(CSC)-like cell population may be the main factor for breast cancer metastasis.Therefore,targeted th... BACKGROUND Breast cancer is a common malignant tumor that seriously threatens women’s health.Breast cancer stem cell(CSC)-like cell population may be the main factor for breast cancer metastasis.Therefore,targeted therapy for CSCs has great potential significance.Hypoxia-inducible factor is a transcription factor widely expressed in tumors.Studies have shown that down-regulation of the hypoxia signaling pathway inhibits tumor stem cell self-renewal and increases the sensitivity of stem cells to radiotherapy and chemotherapy mediated by hypoxiainducible factor-2α(HIF-2α).However,the specific mechanism remains unclear and further research is necessary.AIM To investigate the effect of HIF-2αdown-regulation on stem cell markers,microsphere formation,and apoptosis in breast cancer cell line MDA-MB-231 under hypoxia and its possible mechanism.METHODS Immunohistochemistry was used to detect the expression of HIF-2αand CD44 in triple-negative breast cancer(TNBC)and non-TNBC tissues.Double-labeling immunofluorescence was applied to detect the co-expression of HIF-2αand CD44 in MDA-MB-231 cells and MCF-7 cells.HIF-2αwas silenced by RNA interference,and the expression of CD44 and transfection efficiency were detected by real-time fluorescent quantitative PCR.Further,flow cytometry,TdT-mediated X-dUTP nick end labeling,and mammosphere formation assays were used to evaluate the effect of HIF-2αon CSCs and apoptosis.The possible mechanisms were analyzed by Western blot.RESULTS The results of immunohistochemistry showed that HIF-2αwas highly expressed in both TNBC and non-TNBC,while the expression of CD44 in different molecular types of breast cancer cells was different.In in vitro experiments,it was found that HIF-2αand CD44 were expressed almost in the same cell.Compared with hypoxia+negative-sequence control,HIF-2αsmall interfering ribonucleic acid transfection can lower the expression of HIF-2αand CD44 mRNA(P<0.05),increase the percentage of apoptotic cells(P<0.05),and resulted in a reduction of CD44+/CD24−population(P<0.05)and mammosphere formation(P<0.05)in hypoxic MDA-MB-231 cells.Western blot analysis revealed that phosphorylated protein-serine-threonine kinase(p-AKT)and phosphorylated mammalian target of rapamycin(p-mTOR)levels in MDA-MB-231 decreased significantly after HIF-2αsilencing(P<0.05).CONCLUSION Down-regulation of HIF-2αexpression can inhibit the stemness of human breast cancer MDA-MB-231 cells and promote apoptosis,and its mechanism may be related to the CD44/phosphoinosmde-3-kinase/AKT/mTOR signaling pathway. 展开更多
关键词 breast cancer Hypoxia-inducible factor-2α cancer stem cells CD44
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Adjuvant treatment for triple-negative breast cancer: a retrospective study of immunotherapy with autologous cytokine-induced killer cells in 294 patients 被引量:7
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作者 Yuhan Zhang Shuaibing Wang +3 位作者 Beibei Yang Su Lu Yiyi Du Hong Liu 《Cancer Biology & Medicine》 SCIE CAS CSCD 2019年第2期350-360,共11页
Objective: To examine the efficacy and safety of a sequential combination of chemotherapy and autologous cytokine-induced killer(CIK) cell treatment in triple-negative breast cancer(TNBC) patients.Methods: A total of ... Objective: To examine the efficacy and safety of a sequential combination of chemotherapy and autologous cytokine-induced killer(CIK) cell treatment in triple-negative breast cancer(TNBC) patients.Methods: A total of 294 post-surgery TNBC patients participated in the research from January 1, 2009 to January 1, 2015. After adjuvant chemotherapy, autologous CIK cells were introduced in 147 cases(CIK group), while adjuvant chemotherapy alone was used to treat the remaining 147 cases(control group). The major endpoints of the investigation were the disease-free survival(DFS) and overall survival(OS). Additionally, the side effects of the treatment were evaluated.Results: In the CIK group, the DFS and OS intervals of the patients were significantly longer than those of the control group(DFS:P = 0.047;OS: P = 0.007). The multivariate analysis demonstrated that the TNM(tumor-node-metastasis) stage and adjuvant CIK treatment were independent prognostic factors for both DFS [hazard ratio(HR)= 0.520, 95% confidence interval(CI):0.271-0.998, P = 0.049;HR = 1.449, 95% CI:1.118-1.877, P = 0.005, respectively] and OS(HR=0.414, 95% CI:0.190-0.903, P = 0.027;HR= 1.581, 95% CI:1.204-2.077, P = 0.001, respectively) in patients with TNBC. Additionally, longer DFS and OS intervals were associated with increased number of CIK treatment cycles(DFS: P = 0.020;OS: P = 0.040). The majority of the patients who benefitted from CIK cell therapy were relatively early-stage TNBC patients.Conclusion: Chemotherapy in combination with adjuvant CIK could be used to lower the relapse and metastasis rate, thus effectively extending the survival time of TNBC patients, especially those at early stages. 展开更多
关键词 IMMUNOTHERAPY triple-negative breast cancer cytokine-induced KILLER cell prognosis disease-free SURVIVAL overall SURVIVAL
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Why natural killer cells in triple negative breast cancer? 被引量:1
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作者 Mustafa Abdel-Latif Rana Ahmed Youness 《World Journal of Clinical Oncology》 CAS 2020年第7期464-476,共13页
The triple-negative subtype of breast cancer(TNBC)has the bleakest prognosis,owing to its lack of either hormone receptor as well as human epidermal growth factor receptor 2.Henceforth,immunotherapy has emerged as the... The triple-negative subtype of breast cancer(TNBC)has the bleakest prognosis,owing to its lack of either hormone receptor as well as human epidermal growth factor receptor 2.Henceforth,immunotherapy has emerged as the front-runner for TNBC treatment,which avoids potentially damaging chemotherapeutics.However,despite its documented association with aggressive side effects and developed resistance,immune checkpoint blockade continues to dominate the TNBC immunotherapy scene.These immune checkpoint blockade drawbacks necessitate the exploration of other immunotherapeutic methods that would expand options for TNBC patients.One such method is the exploitation and recruitment of natural killer cells,which by harnessing the innate rather than adaptive immune system could potentially circumvent the downsides of immune checkpoint blockade.In this review,the authors will elucidate the advantageousness of natural killer cell-based immuno-oncology in TNBC as well as demonstrate the need to more extensively research such therapies in the future. 展开更多
关键词 triple negative breast cancer Natural killer cells Immune checkpoint blockades Programmed death-ligand 1 Cytotoxic T-lymphocyte-associated protein 4 Natural killer lectin-like group 2 member D
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Effects of TAM-derived exosomes on migration and invasion of MDA-MB- 231 cells in triple negative breast cancer
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作者 Yu Liu Chao-Qun Wang +4 位作者 Jiang-Zheng Zeng Bing-Yu Gao Fang-Fang Gao Yu Wang Bin Chen 《Journal of Hainan Medical University》 2021年第9期26-29,共4页
Objective:To investigate the effects of exosomes derived from tumor-associated macrophages(TAMs)on migration and invasion of MDA-MB-231 cells in triple negative breast cancer.Methods:The MDA-MB-231 cells,a human breas... Objective:To investigate the effects of exosomes derived from tumor-associated macrophages(TAMs)on migration and invasion of MDA-MB-231 cells in triple negative breast cancer.Methods:The MDA-MB-231 cells,a human breast cancer cell line,were divided into the experimental group and the blank control group.The exosomes were isolated from the supernatant of human peripheral blood mononuclear cells(THP-1)by a multi-step ultracentrifugal procedure.The effects of exosomes on migration and invasion of MDAMB-231 cells were studied by endocytosis assay of exosomes,Transwell migration assay and Celigo scratch assay.Results:Exosomes were ingested and endocytosed by MDAMB-231 cells,brought into the cytoplasm at 3h and enriched significantly at 6h.Compared with the blank control group,the number of metastatic cells in the Transwell compartment(241±3.35)and its variation relative to normal cells(144±2.33)in the experimental group were significantly increased(P<0.05).The 24 h migration rate of MDA-MB-231 cells treated with exosomes in the scratch assay showed similar results(39.86±3.47 in the experimental group vs.24.48±2.97 in the control group,P<0.05).Conclusion:TAM-derived exosomes can be ingested and endocytosed by MDA-MB-231 cells,and promote their migration and invasion in vitro. 展开更多
关键词 Tumor-associated macrophages triple negative breast cancer EXOSOME ENDOCYTOSIS MIGRATION INVASION
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Game-changing insights on vertebral skeletal stem cells in bone metastasis and therapeutic horizons
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作者 QIUQIANG CHEN XIAOLEI ZHAO WENXUE MA 《Oncology Research》 SCIE 2024年第1期95-98,共4页
Greenblatt and his team have unveiled vertebral skeletal stem cells(vSSCs)as a critical player in the landscape of bone metastasis.This commentary delves into the transformative discoveries surrounding vSSCs,emphasizi... Greenblatt and his team have unveiled vertebral skeletal stem cells(vSSCs)as a critical player in the landscape of bone metastasis.This commentary delves into the transformative discoveries surrounding vSSCs,emphasizing their distinct role in bone metastasis compared to other stem cell lineages.We illuminate the unique properties and functions of vSSCs,which may account for the elevated susceptibility of vertebral bones to metastatic invasion.Furthermore,we explore the exciting therapeutic horizons opened by this newfound understanding.These include potential interventions targeting vSSCs,modulation of associated signaling pathways,and broader implications for the treatment and management of bone metastasis.By shedding light on these game-changing insights,we hope to pave the way for novel strategies that could revolutionize the prognosis and treatment landscape for cancer patients with metastatic bone disease. 展开更多
关键词 Vertebral skeletal stem cells(vSSCs) stem cell research Metastasis breast prostate and lung cancers Spinal metastasis Matthew Greenblatt Genetic expressions
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Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer in vitro and in vivo 被引量:10
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作者 Lei-lei FU Yu-qian ZHAO Bo LIU 《中国药理学与毒理学杂志》 CAS CSCD 北大核心 2017年第10期957-958,共2页
OBJECTIVE To discover a small molecule targeting ULK1-modulated cell death of triple negative breast cancer and exploreits potential mechanisms.METHODS ULK1 expression was analyzed by The Cancer Genome Atlas(TCGA)anal... OBJECTIVE To discover a small molecule targeting ULK1-modulated cell death of triple negative breast cancer and exploreits potential mechanisms.METHODS ULK1 expression was analyzed by The Cancer Genome Atlas(TCGA)analysis and tissue microarray(TMA)analysis.ULK1agonist was designed by using in silico screening,as well as modified by chemical synthesis and screened by kinase and anti-proliferative activities.The amino acid residues that key to the activation site of LYN-1604 were determined by site-directed mutagenesis,as well as in vitro kinase assay and ADP-Glo kinase assay.The mechanisms of LYN-1604 induced cell death were investigated by fluorescence microscope,western blotting,flow cytometry analysis,immunocytochemistry,as well as si RNA and GFP-m RFP-LC3 plasmid transfections.Potential ULK1 interactors were discovered by performing comparative microarray analysis and the therapeutic effect of LYN-1604 was assessed by xenograft breast cancer mouse model.RESULTS We found that ULK1 was remarkably downregulated in breast cancer tissue samples,especial y in triple negative breast cancer(TNBC).32 candidate smal molecules were synthesized,and we discovered a small molecule named LYN-1604 as the best candidate ULK1agonist.Additionally,we identified that three amino acid residues(LYS50,LEU53 and TYR89)were key to the activation site of LYN-1604 and ULK1.Subsequently,we demonstrated that LYN-1604 could induce autophagy-associated cell death via ULK complex(ULK1-m ATG13-FIP200-ATG101)in MDA-MB-231 cells.We also found that LYN-1604 induced cell death involved in ATF3,RAD21 and caspase 3,accompanied with autophagy and apoptosis.Moreover,we demonstrated that LYN-1604 had a good therapeutic potential on TNBC by targeting ULK1-modulated cell death in vivo.CONCLUSION We discovered a small molecule(LYN-1604)has therapeutic potential by targeting ULK1-modulated cell death associated with autophagy and apoptosis of TNBC in vitro and in vivo,which could be utilized as a new anti-TNBC drug candidate. 展开更多
关键词 UNC-51-like kinase 1(ULK1) cell death AUTOPHAGY ULK1 agonist triple negative breast cancer(TNBC)
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Effects of Notch-1 Down-regulation on Malignant Behaviors of Breast Cancer Stem Cells 被引量:8
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作者 彭功玲 田野 +6 位作者 逯翀 郭辉 赵向旺 郭雅文 王龙强 杜秋丽 刘春萍 《Journal of Huazhong University of Science and Technology(Medical Sciences)》 SCIE CAS 2014年第2期195-200,共6页
This study examined the effect of Notch-1 signaling on malignant behaviors of breast cancer cells by regulating breast cancer stem cells (BCSCs). BCSCs were enriched by using serum-free me- dium and knocked out of N... This study examined the effect of Notch-1 signaling on malignant behaviors of breast cancer cells by regulating breast cancer stem cells (BCSCs). BCSCs were enriched by using serum-free me- dium and knocked out of Notch-1 by using a lentiviral vector. Real-time polymerase chain reaction (RT-PCR) and Western blotting were used to detect the Notch-1 expression levels in breast cancer cell lines and BCSCs, and fl0w cytometry to detect the proportion of BCSCs in BCSC spheres. The BCSC self-renewal, migration, invasion, and tumorigenicity were examined by the tumor microsphere-forming assay and transwell assay and after xenotransplantation. The results showed that the Notch-1 silencing reduced the number of BCSC spheres, the proportion of BCSCs, and the number of cells penetrating through the transwell membrane. It also decreased the size of tumors that were implanted in the nude mice. These results suggest that Notch-1 signaling is intimately linked to the behaviors of BCSCs. Blocking Notch-1 signaling can inhibit the malignant behaviors of BCSCs, which may provide a prom- ising therapeutical approach for breast cancer. 展开更多
关键词 NOTCH-1 breast cancer cancer stem cells tumor metastasis TUMORIGENESIS
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Metabolic reprogramming in triple-negative breast cancer 被引量:13
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作者 Zhanyu Wang Qianjin Jiang Chenfang Dong 《Cancer Biology & Medicine》 SCIE CAS CSCD 2020年第1期44-59,共16页
Since triple-negative breast cancer(TNBC)was first defined over a decade ago,increasing studies have focused on its genetic and molecular characteristics.Patients diagnosed with TNBC,compared to those diagnosed with o... Since triple-negative breast cancer(TNBC)was first defined over a decade ago,increasing studies have focused on its genetic and molecular characteristics.Patients diagnosed with TNBC,compared to those diagnosed with other breast cancer subtypes,have relatively poor outcomes due to high tumor aggressiveness and lack of targeted treatment.Metabolic reprogramming,an emerging hallmark of cancer,is hijacked by TNBC to fulfill bioenergetic and biosynthetic demands;maintain the redox balance;and further promote oncogenic signaling,cell proliferation,and metastasis.Understanding the mechanisms of metabolic remodeling may guide the design of metabolic strategies for the effective intervention of TNBC.Here,we review the metabolic reprogramming of glycolysis,oxidative phosphorylation,amino acid metabolism,lipid metabolism,and other branched pathways in TNBC and explore opportunities for new biomarkers,imaging modalities,and metabolically targeted therapies. 展开更多
关键词 Metabolic reprogramming triple-negative breast cancer aerobic glycolysis Warburg effect cancer stem cell targeted therapy
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Biomarkers in triple negative breast cancer:A review 被引量:14
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作者 Budhi S Yadav Priyanka Chanana Swaty Jhamb 《World Journal of Clinical Oncology》 CAS 2015年第6期252-263,共12页
Breast cancer is an intrinsically heterogeneous disease. In the world about 1 million cases of breast cancer are diagnosed annually and more than 170000 are triplenegative. Characteristic feature of triple negative br... Breast cancer is an intrinsically heterogeneous disease. In the world about 1 million cases of breast cancer are diagnosed annually and more than 170000 are triplenegative. Characteristic feature of triple negative breast cancer(TNBC) is that it lacks expression of oestrogen,progesterone and human epidermal growth factor receptor-2/neu receptors. They comprise 15%-20% of all breast cancers. We did a systematic review of Pub Med and conference databases to identify studies published on biomarkers in TNBC. We included studies with biomarkers including: Epidermal growth factor receptor,vascular endothelial growth factor,c-Myc,C-kit and basal cytokeratins,Poly(ADP-ribose) polymerase-1,p53,tyrosinase kinases,m-TOR,heat and shock proteins and TOP-2A in TNBC. We also looked for studies published on synthetic lethality and inhibition of angiogenesis,growth,and survival pathways. TNBC is a complex disease subtype with many subclasses. Majority TNBC have a basal-like molecular phenotype by gene expression profiling. Their clinical and pathologic features overlap with hereditary BRCA1 related breast cancers. Management of these tumours is a challenge to the clinician because of its aggressive behaviour,poor outcome,and absence of targeted therapies. As the complexity of this disease is being simplified over time new targets are also being discovered for the treatment of this disease. There are many biomarkers in TNBC being used in clinical practice. Biomarkers may be useful as prognostic or predictive indicators as well as suggest possible targets for novel therapies. Many targeted agents are being studied for treatment of TNBC. 展开更多
关键词 triple negative breast cancer EPIDERMAL GROWTH FACTOR receptor VASCULAR ENDOTHELIAL GROWTH FACTOR p53 CYCLIN
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Efficacy of platinum in advanced triple-negative breast cancer with germline BRCA mutation determined by next generation sequencing 被引量:8
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作者 Nan Wang Kun Li +10 位作者 Wenfa Huang Weiyao Kong Xiaoran Liu Weijie Shi Feng Xie Hanfang Jiang Guohong Song Lijun Di Quanren Wang Jianjun Yu Huiping Li 《Chinese Journal of Cancer Research》 SCIE CAS CSCD 2020年第2期149-162,共14页
Objective:To compare the efficacy of platinum-and non-platinum-based regimens as first-line treatment for advanced triple-negative breast cancer(TNBC)and analyze the relationship between their efficacy and BRCA gene s... Objective:To compare the efficacy of platinum-and non-platinum-based regimens as first-line treatment for advanced triple-negative breast cancer(TNBC)and analyze the relationship between their efficacy and BRCA gene status.Methods:Retrospectively analyze clinical data of 220 patients diagnosed pathologically with advanced TNBC and treated at the Department of Breast Oncology,Peking University Cancer Hospital from 2013 to 2018 and evaluate the efficacy of chemotherapy.A total of 114 patients had BRCA1/2 gene tested by next generation sequencing(NGS)using peripheral blood,and we analyzed the correlation between their efficacy and BRCA1/2 gene status.Results:Non-platinum-based chemotherapy(NPCT)was administered to 129 and platinum-based chemotherapy(PBCT)to 91 study patients.The clinical benefit rate(CBR)and median progression-free survival(PFS)were not statistically different between NPCT and PBCT groups.The median overall survival(OS)was 30.0 and 22.5 months for PBCT and NPCT group,respectively[P=0.090,hazard ratios(HR)=0.703].BRCA status was assessed in 114 patients,14 of whom had deleterious germline BRCA1/2(g BRCA)mutations(seven in each group).In PBCT group,the CBR was 85.7%and 35.1%for patients with and without deleterious g BRCA mutations,respectively(P=0.039).The median PFS were 14.9 and 5.3 months and median OS were 26.5 and 15.5 months for patients with and without deleterious g BRCA mutations,respectively(P=0.001,P=0.161,respectively).Patients in PBCT group had significantly greater rates of grade 3-4 anemia(5.5%vs.0%)and thrombocytopenia(8.8%vs.0%),whereas palmar-plantar erythrodysesthesia(12.4%vs.0%)and peripheral neuropathy(8.6%vs.1.1%)occurred more frequently in NPCT group.Conclusions:Platinum-based regimens are more effective in patients with deleterious g BRCA mutations,but no difference in patients without BRCA gene mutations,so non-platinum is an option in patients without BRCA gene mutations considering the toxicity and side effect.And we recommend that patients with advanced TNBC should have BRCA gene test. 展开更多
关键词 Advanced breast cancer triple negative BRCA mutation next-generation sequencing PLATINUM EFFICACY
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STAT3 mediates resistance of CD44^+CD24^(-/low) breast cancer stem cells to tamoxifen in vitro 被引量:6
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作者 Xiaoyan Wang Guozhu Wang +5 位作者 Yi Zhao Xiaoan Liu Qiang Ding Jingping Shi Yin Ding Shui Wang 《The Journal of Biomedical Research》 CAS 2012年第5期325-335,共11页
We sought to determine whether STAT3 mediated tamoxifen resistance of breast cancer stem cells in vitro.The capacities for mammosphere formation and STAT3 expression of CD44+CD24-/low MCF-7 and MCF-7 were observed.Th... We sought to determine whether STAT3 mediated tamoxifen resistance of breast cancer stem cells in vitro.The capacities for mammosphere formation and STAT3 expression of CD44+CD24-/low MCF-7 and MCF-7 were observed.The CD44+CD24-/low subpopulation ratio and its sensitivity to adriamycin were analyzed in MCF-7 and TAM resistant(TAM-R) cells.Cell cycle,apoptosis,STAT3 and phospho-STAT3 changes were observed af-ter treatment with tamoxifen.Small interference RNA-mediated knockdown of STAT3 in TAM-R cells was also performed.CD44+CD24-/low MCF-7 showed higher capacities for mammosphere formation and STAT3 expression than total MCF-7.The CD44+CD24-/low subpopulation was also upregulated in TAM-R cells with less sensitivity to adriamycin than MCF-7.Cell cycle changes,anti-apoptotic effects and STAT3 changes were also found.Mean-while,the knock-down of STAT3 in TAM-R resulted in an increase in sensitivity to tamoxifen.It is concluded that STAT3 plays an essential role in breast cancer stem cells,which correlated with tamoxifen resistance. 展开更多
关键词 STAT3 breast cancer cancer stem cells tamoxifen drug resistance
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Triple negative breast cancer: special histological types and emerging therapeutic methods 被引量:5
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作者 Lu Cao Yun Niu 《Cancer Biology & Medicine》 SCIE CAS CSCD 2020年第2期293-306,共14页
Triple negative breast cancer(TN BC)is a complex and malignant breast cancer subtype that lacks expression of the estrogen receptor(ER),progesterone receptor(PR)and human epidermal growth factor receptor 2(H ER2),ther... Triple negative breast cancer(TN BC)is a complex and malignant breast cancer subtype that lacks expression of the estrogen receptor(ER),progesterone receptor(PR)and human epidermal growth factor receptor 2(H ER2),thereby making therapeutic targeting difficult.TNBC is generally considered to have high malignancy and poor prognosis.However,patients diagnosed with certain rare histomorphologic subtypes of TNBC have better prognosis than those diagnosed with typical triple negative breast cancer.In addition,with the discovery and development of novel treatment targets such as the androgen receptor(AR),PI3K/AKT/mTOR and AMPK signaling pathways,as well as emerging immunotherapies,the therapeutic options for TNBC are increasing.In this paper,we review the literature on various histological types of TNBC and focus on newly developed therapeutic strategies that target and potentially affect molecular pathways or emerging oncogenes,thus providing a basis for future tailored therapies focused on the mutational aspects of TNBC. 展开更多
关键词 triple negative breast cancer pathological subtype androgen receptor IMMUNOTHERAPY targeted therapy
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