Objective： To explore the effects of Janus activated kinase （JAK） inhibitor AG490 on the phosphorylation of extracellular signal regulated protein kinase （ERK） in human breast cancer cells MDA-MB-231 and the role...Objective： To explore the effects of Janus activated kinase （JAK） inhibitor AG490 on the phosphorylation of extracellular signal regulated protein kinase （ERK） in human breast cancer cells MDA-MB-231 and the roles of JAK in the invasion and metastasis of the human breast cancer cells through ERK signaling transduction pathways. Methods： MDA-MB-231 cells were treated with 20 μmol/L, 40 μmol/L, 80 μmol/L Janus kinase inhibitor AG490 for 24, 48 and 72 h. Proliferation and adhesion of MDA-MB-231 cells to matrigel were measured with MTT assay. When treated with 40 μmol/L AG490 for 24 h, the expressions of P-ERK and MMP-9 of cells were detected by Western-blot and invasion and metastasis of MDA-MB-231 cells were evaluated with transwell chamber. Results： After being treated with 20 μmol/L, 40 μ/L, 80 μmol/L AG490 for 24, 48 and 72 h, the proliferation of MDA-MB-231 cells was inhibited in a dose-and time-dependent manner. MDA-MB-231 cells treated with 40 μmol/L AG490 for 30, 60, 90 and 120 rain resulted in the increasing adhesion of cells to Matrigel in a time-dependent manner. However, capacity of adhesion in the group treated with AG490 was significantly decreased in comparison with the control group （P〈0.01）. The expression level of P-ERK and MMP-9 were decreased when treated with AG490. After treatment with 40 μmol/L AG490, in invasion assay, the number of cells in AG490 treated group to migrate to filter coated with Matrigel was reduced compared with control group （P〈0.05） Meanwhile, in migration assay, the number of cells in AG490 treated group to migrate to filter was also decreased compared with control group （P〈0.05）. Conclusion： Our study indicates that JAK kinase could affect the activity of ERK signal transduction pathway through the phosphorylation of ERK. The inhibitory effects of JAK kinase on MMP-9 expression and invasion of breast cancer cells were associated with the down-regulation of the ERK signaling pathway.展开更多
Objective： To explore the effects of neuregulins on ErbB2 receptor signal transduction pathway activation, and invasion and metastasis of non-overexpression ErbB2 breast cancer cell MDA-MB-231. Methods： The express...Objective： To explore the effects of neuregulins on ErbB2 receptor signal transduction pathway activation, and invasion and metastasis of non-overexpression ErbB2 breast cancer cell MDA-MB-231. Methods： The expressions of neuregulin were detected by immunocytochemistry and Western blot. MDA-MB-231 cells were treated with ErbB2 kinase inhibitor AG825. Proliferations were measured with MTT assay. Invasion and metastasis of MDA-ME-231 cells were evaluated with transwell chamber. The enzyme activities of MMP-2 and MMP-9 were detected by gelatin zymography. The expressions of MMP-2 and HIF-1α were detected by Western blot. Results： MDA-MB-231 cells expressed a relatively higher level of neuregulin. In Western blot, the positive reaction band was found at 44KD which coincides with the molecular weight of NRG. When MDA-MB-231 cells were treated with AG825, the proliferation was inhibited in a time-dose-dependent manner （P〈0.01）, invasion and metastasis were also depressed （P〈0.05）. The enzyme activities of MMP-2 and MMP-9 were lower （P〈0.05）. The expression levels of MMP-2 and HIF-lct were decreased （P〈0.05）. Conclusion： Our study indicates that neuregulins are synthesized in MDA-MB-231 cells as transmembrane proteins, neuregulins could activate ErbB2 receptor signal transduction pathway by autocrine or paracrine secretion, and induce invasion and metastasis of MDA-MB-231 cells.展开更多
Objective:To investigate the relationship between CYPIA1 genetic polymorphisms and the invasion and metastasis of breast cancer.Methods:The CYP1A1 gene polymorphism(an T-C transversion at nucleotide position 3801)was ...Objective:To investigate the relationship between CYPIA1 genetic polymorphisms and the invasion and metastasis of breast cancer.Methods:The CYP1A1 gene polymorphism(an T-C transversion at nucleotide position 3801)was detected by the polymerase chain reaction and restriction fragment length polymorphism in 80 cases with breast cancer and 60 samples of normal breast tissue.The difference in genotypic distribution frequency between the groups,the correlation between the genotypes and the factors related to prognosis were analyzed.Results:The incidence of homozygous and variant genotypes had no difference between the breast cancer group and controls group(P=0.746).The proportion of variant genotype increased as clinical stage(P=0.006)advanced,as well as with increased numbers of lymph node metastases(P=0.010).Conclusions:In patients with breast cancer there is a correlation between the CYP1A1 CC allele and some factors indicating poor prognosis,including more lymph node metastases as well as a more advanced clinical stage.展开更多
Distant metastasis to specific target organs is responsible for over 90%of breast cancer?related deaths,but the underlying molecular mechanism is unclear.Mounting evidence suggests that the interplay between breast ca...Distant metastasis to specific target organs is responsible for over 90%of breast cancer?related deaths,but the underlying molecular mechanism is unclear.Mounting evidence suggests that the interplay between breast cancer cells and the target organ microenvironment is the key determinant of organ?specific metastasis of this lethal disease.Here,we highlight new findings and concepts concerning the emerging role of the tumor microenvironment in breast cancer metastasis;we also discuss potential therapeutic intervention strategies aimed at targeting compo?nents of the tumor microenvironment.展开更多
Estrogen disrupting chemicals are environmental compounds which mimic, antagonize or interfere in the action of physiological estrogens. They occur naturally (plant phytoestrogens) but the majority are man-made compou...Estrogen disrupting chemicals are environmental compounds which mimic, antagonize or interfere in the action of physiological estrogens. They occur naturally (plant phytoestrogens) but the majority are man-made compounds, which, through their use in agricultural, industrial and consumer products, have become widely present in human tissues including breast tissue. Since exposure to estrogen is a risk factor for breast cancer, estrogen disrupting chemicals may also contribute to breast cancer development. This review discusses evidence implicating estrogen disrupting chemicals in increasing migratory and invasive activity of breast epithelial cells, in epithelial-to-mesenchymal transition, and in growth of breast tumours at metastatic sites as well as the primary site. Mechanisms may be through the ability of such chemicals to bind to estrogen receptors, but unlike for proliferation, effects on cell migration and invasion are not limited to estrogen receptor-mediated mechanisms. Furthermore, whilst effects on proliferation can be measured within hours/days of adding an estrogen disrupting chemical to estrogen-responsive breast cancer cells, effects on cell migration occur after longer times (weeks). Most studies have focused on individual chemicals, but there is now a need to consider the environmentally relevant effects of long-term, low-dose exposure to complex mixtures of estrogen disrupting chemicals on mechanisms of metastasis.展开更多
Objective:Triple-negative breast cancer(TNBC)is highly metastatic,and there is an urgent unmet need to develop novel therapeutic strategies leading to the new drug discoveries against metastasis.The transforming growt...Objective:Triple-negative breast cancer(TNBC)is highly metastatic,and there is an urgent unmet need to develop novel therapeutic strategies leading to the new drug discoveries against metastasis.The transforming growth factor-β(TGF-β)is known to promote the invasive and migratory potential of breast cancer cells through induction of epithelial–mesenchymal transition(EMT)via the ERK/NF-κB/Snail signaling pathway,leading to breast cancer metastasis.Targeting this pathway to revert the EMT would be an attractive,novel therapeutic strategy to halt breast cancer metastasis.Methods:Effects of enterolactone(EL)on the cell cycle and apoptosis were investigated using flow cytometry and a cleaved caspase-3 enzyme-linked immunosorbent assay(ELISA),respectively.Effects of TGF-βinduction and EL treatment on the functional malignancy of MDA-MB-231 breast cancer cells were investigated using migration and chemo-invasion assays.The effects of EL on EMT markers and the ERK/NF-κB/Snail signaling pathway after TGF-βinduction were studied using confocal microscopy,quantitative reverse transcription polymerase chain reaction(q RT-PCR),Western blot,and flow cytometry.Results:Herein,we report that EL exhibits a significant antimetastatic effect on MDA-MB-231 cells by almost reverting the TGF-β-induced EMT in vitro.EL downregulates the mesenchymal markers N-cadherin and vimentin,and upregulates the epithelial markers E-cadherin and occludin.It represses actin stress fiber formation via inhibition of mitogen-activated protein kinase p-38(MAPK-p38)and cluster of differentiation 44(CD44).EL also suppresses ERK-1/2,NF-κB,and Snail at the m RNA and protein levels.Conclusions:Briefly,EL was found to inhibit TGF-β-induced EMT by blocking the ERK/NF-κB/Snail signaling pathway,which is a promising target for breast cancer metastasis therapy.展开更多
BACKGROUND Gastrointestinal metastasis of breast cancer is rare,and clinicians may not have previously encountered this disease in clinical practice.CASE SUMMARY We report a patient with invasive lobular carcinoma of ...BACKGROUND Gastrointestinal metastasis of breast cancer is rare,and clinicians may not have previously encountered this disease in clinical practice.CASE SUMMARY We report a patient with invasive lobular carcinoma of the breast who developed gastrointestinal metastasis two years after modified radical surgery.Mild elevation of carbohydrate antigen 15-3 was observed in the patient at an early stage;however,diagnosis and treatment were delayed due to non-specific clinical manifestations and no identifiable metastasis observed on imaging.CONCLUSION Clinicians should pay attention to gastrointestinal metastasis of breast cancer,especially invasive lobular carcinoma of the breast.展开更多
Epithelial-mesenchymal transition (EMT) is a plastic and reversible process, essential for development and tissue homeostasis. Under pathological conditions, EMT causes induction of tumor growth, angiogenesis and meta...Epithelial-mesenchymal transition (EMT) is a plastic and reversible process, essential for development and tissue homeostasis. Under pathological conditions, EMT causes induction of tumor growth, angiogenesis and metastasis. According to its reversible nature, the EMT program is associated with vast epigenetic changes. Targeting the epigenetic network that controls the EMT pathway in disease progression is a novel promising strategy to fight cancer metastasis. The impact of alterations in histone methylation in cancer has led to the identification of histone methyltransferases and demethylases as promising novel targets for therapy. Specifically, the lysine specific demethylase 1 (LSD1, also known as KDM1A) plays a pivotal role in the regulation of EMT. Here we present an overview of the causative role of LSD1 in the EMT process, summarizing recent findings on its emerging functions in cell migration and invasion in breast cancer.展开更多
背景腋窝淋巴结负荷对乳腺癌患者预后具有一定的提示作用,腋窝高淋巴结负荷(axillary high nodal burden,AHNB)提示预后较差,通常需行腋窝淋巴结清扫和辅助治疗。免疫炎症指标被证明与多种肿瘤预后相关,但其与三阴性乳腺癌腋窝淋巴结负...背景腋窝淋巴结负荷对乳腺癌患者预后具有一定的提示作用,腋窝高淋巴结负荷(axillary high nodal burden,AHNB)提示预后较差,通常需行腋窝淋巴结清扫和辅助治疗。免疫炎症指标被证明与多种肿瘤预后相关,但其与三阴性乳腺癌腋窝淋巴结负荷有无关联尚不确定。目的分析免疫炎症指标对三阴性乳腺癌发生腋窝淋巴结转移和AHNB的预测价值,探讨腋窝淋巴结转移及高负荷的关联因素。方法收集本中心乳腺外科2010年1月—2023年1月收治的可手术的三阴性乳腺癌患者,分析中性粒细胞/淋巴细胞比值(neutrophil to lymphocyte ratio,NLR)、血小板/淋巴细胞比值(platelet to lymphocyte ratio,PLR)、淋巴细胞/单核细胞比值(lymphocyte to monocyte ratio,LMR)、系统性免疫性炎症指数(systemic immune-inflammation index,SII)和泛免疫炎症指数(pan immune-inflammation value,PIV)等免疫炎症指标与三阴性乳腺癌患者腋窝淋巴结转移和AHNB的关联性。结果纳入408例三阴性乳腺癌患者,其中包括255例(62.5%)腋窝淋巴结阴性的患者,153例淋巴结阳性患者,后者包括78例(19.12%)腋窝低淋巴结负荷(axillary low nodal burden,ALNB)患者和75例(18.38%)AHNB患者。单因素Logistic回归分析提示,组织学分级、病理类型、肿瘤大小、脉管侵犯、NLR与三阴性乳腺癌发生腋窝淋巴结转移相关;年龄、组织学分级、肿瘤大小、脉管侵犯与发生AHNB相关(P>0.05)。多因素Logistic回归分析提示,三阴性乳腺癌发生腋窝淋巴结转移的独立关联因素是组织学分级G3(OR=2.081,95%CI:1.334~3.245)、肿瘤≥2 cm(OR=1.658,95%CI:1.083~2.539)、有脉管侵犯(OR=2.884,95%CI:1.562~5.324)。AHNB的独立关联因素是组织学G3(OR=2.391,95%CI:1.310~4.366)、肿瘤≥2 cm(OR=1.968,95%CI:1.130~3.427)、有脉管侵犯(OR=4.592,95%CI:2.433~8.665)。结论组织学分级、肿瘤大小、脉管侵犯对三阴性乳腺癌患者的腋窝淋巴结转移和负荷水平具有一定的提示作用,而免疫炎症指标对腋窝淋巴结负荷的预测能力有限。展开更多
基金supported by the Scientific Research Foundation of Chonging Medical University (No. XBYB2007089).
文摘Objective： To explore the effects of Janus activated kinase （JAK） inhibitor AG490 on the phosphorylation of extracellular signal regulated protein kinase （ERK） in human breast cancer cells MDA-MB-231 and the roles of JAK in the invasion and metastasis of the human breast cancer cells through ERK signaling transduction pathways. Methods： MDA-MB-231 cells were treated with 20 μmol/L, 40 μmol/L, 80 μmol/L Janus kinase inhibitor AG490 for 24, 48 and 72 h. Proliferation and adhesion of MDA-MB-231 cells to matrigel were measured with MTT assay. When treated with 40 μmol/L AG490 for 24 h, the expressions of P-ERK and MMP-9 of cells were detected by Western-blot and invasion and metastasis of MDA-MB-231 cells were evaluated with transwell chamber. Results： After being treated with 20 μmol/L, 40 μ/L, 80 μmol/L AG490 for 24, 48 and 72 h, the proliferation of MDA-MB-231 cells was inhibited in a dose-and time-dependent manner. MDA-MB-231 cells treated with 40 μmol/L AG490 for 30, 60, 90 and 120 rain resulted in the increasing adhesion of cells to Matrigel in a time-dependent manner. However, capacity of adhesion in the group treated with AG490 was significantly decreased in comparison with the control group （P〈0.01）. The expression level of P-ERK and MMP-9 were decreased when treated with AG490. After treatment with 40 μmol/L AG490, in invasion assay, the number of cells in AG490 treated group to migrate to filter coated with Matrigel was reduced compared with control group （P〈0.05） Meanwhile, in migration assay, the number of cells in AG490 treated group to migrate to filter was also decreased compared with control group （P〈0.05）. Conclusion： Our study indicates that JAK kinase could affect the activity of ERK signal transduction pathway through the phosphorylation of ERK. The inhibitory effects of JAK kinase on MMP-9 expression and invasion of breast cancer cells were associated with the down-regulation of the ERK signaling pathway.
文摘Objective： To explore the effects of neuregulins on ErbB2 receptor signal transduction pathway activation, and invasion and metastasis of non-overexpression ErbB2 breast cancer cell MDA-MB-231. Methods： The expressions of neuregulin were detected by immunocytochemistry and Western blot. MDA-MB-231 cells were treated with ErbB2 kinase inhibitor AG825. Proliferations were measured with MTT assay. Invasion and metastasis of MDA-ME-231 cells were evaluated with transwell chamber. The enzyme activities of MMP-2 and MMP-9 were detected by gelatin zymography. The expressions of MMP-2 and HIF-1α were detected by Western blot. Results： MDA-MB-231 cells expressed a relatively higher level of neuregulin. In Western blot, the positive reaction band was found at 44KD which coincides with the molecular weight of NRG. When MDA-MB-231 cells were treated with AG825, the proliferation was inhibited in a time-dose-dependent manner （P〈0.01）, invasion and metastasis were also depressed （P〈0.05）. The enzyme activities of MMP-2 and MMP-9 were lower （P〈0.05）. The expression levels of MMP-2 and HIF-lct were decreased （P〈0.05）. Conclusion： Our study indicates that neuregulins are synthesized in MDA-MB-231 cells as transmembrane proteins, neuregulins could activate ErbB2 receptor signal transduction pathway by autocrine or paracrine secretion, and induce invasion and metastasis of MDA-MB-231 cells.
基金supported by Guangzhou Municipal Science and Technology Support Program(No:10A32060573)
文摘Objective:To investigate the relationship between CYPIA1 genetic polymorphisms and the invasion and metastasis of breast cancer.Methods:The CYP1A1 gene polymorphism(an T-C transversion at nucleotide position 3801)was detected by the polymerase chain reaction and restriction fragment length polymorphism in 80 cases with breast cancer and 60 samples of normal breast tissue.The difference in genotypic distribution frequency between the groups,the correlation between the genotypes and the factors related to prognosis were analyzed.Results:The incidence of homozygous and variant genotypes had no difference between the breast cancer group and controls group(P=0.746).The proportion of variant genotype increased as clinical stage(P=0.006)advanced,as well as with increased numbers of lymph node metastases(P=0.010).Conclusions:In patients with breast cancer there is a correlation between the CYP1A1 CC allele and some factors indicating poor prognosis,including more lymph node metastases as well as a more advanced clinical stage.
基金the Li lab is supported by the National Natural Science Foundation of China(Nos.81372847 and 81572584)the Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning(No.2013-06)+1 种基金the Innovation Program of Shanghai Municipal Education Commission(No.2015ZZ007)the New Investigator Start-up Fund from Fudan University
文摘Distant metastasis to specific target organs is responsible for over 90%of breast cancer?related deaths,but the underlying molecular mechanism is unclear.Mounting evidence suggests that the interplay between breast cancer cells and the target organ microenvironment is the key determinant of organ?specific metastasis of this lethal disease.Here,we highlight new findings and concepts concerning the emerging role of the tumor microenvironment in breast cancer metastasis;we also discuss potential therapeutic intervention strategies aimed at targeting compo?nents of the tumor microenvironment.
文摘Estrogen disrupting chemicals are environmental compounds which mimic, antagonize or interfere in the action of physiological estrogens. They occur naturally (plant phytoestrogens) but the majority are man-made compounds, which, through their use in agricultural, industrial and consumer products, have become widely present in human tissues including breast tissue. Since exposure to estrogen is a risk factor for breast cancer, estrogen disrupting chemicals may also contribute to breast cancer development. This review discusses evidence implicating estrogen disrupting chemicals in increasing migratory and invasive activity of breast epithelial cells, in epithelial-to-mesenchymal transition, and in growth of breast tumours at metastatic sites as well as the primary site. Mechanisms may be through the ability of such chemicals to bind to estrogen receptors, but unlike for proliferation, effects on cell migration and invasion are not limited to estrogen receptor-mediated mechanisms. Furthermore, whilst effects on proliferation can be measured within hours/days of adding an estrogen disrupting chemical to estrogen-responsive breast cancer cells, effects on cell migration occur after longer times (weeks). Most studies have focused on individual chemicals, but there is now a need to consider the environmentally relevant effects of long-term, low-dose exposure to complex mixtures of estrogen disrupting chemicals on mechanisms of metastasis.
文摘Objective:Triple-negative breast cancer(TNBC)is highly metastatic,and there is an urgent unmet need to develop novel therapeutic strategies leading to the new drug discoveries against metastasis.The transforming growth factor-β(TGF-β)is known to promote the invasive and migratory potential of breast cancer cells through induction of epithelial–mesenchymal transition(EMT)via the ERK/NF-κB/Snail signaling pathway,leading to breast cancer metastasis.Targeting this pathway to revert the EMT would be an attractive,novel therapeutic strategy to halt breast cancer metastasis.Methods:Effects of enterolactone(EL)on the cell cycle and apoptosis were investigated using flow cytometry and a cleaved caspase-3 enzyme-linked immunosorbent assay(ELISA),respectively.Effects of TGF-βinduction and EL treatment on the functional malignancy of MDA-MB-231 breast cancer cells were investigated using migration and chemo-invasion assays.The effects of EL on EMT markers and the ERK/NF-κB/Snail signaling pathway after TGF-βinduction were studied using confocal microscopy,quantitative reverse transcription polymerase chain reaction(q RT-PCR),Western blot,and flow cytometry.Results:Herein,we report that EL exhibits a significant antimetastatic effect on MDA-MB-231 cells by almost reverting the TGF-β-induced EMT in vitro.EL downregulates the mesenchymal markers N-cadherin and vimentin,and upregulates the epithelial markers E-cadherin and occludin.It represses actin stress fiber formation via inhibition of mitogen-activated protein kinase p-38(MAPK-p38)and cluster of differentiation 44(CD44).EL also suppresses ERK-1/2,NF-κB,and Snail at the m RNA and protein levels.Conclusions:Briefly,EL was found to inhibit TGF-β-induced EMT by blocking the ERK/NF-κB/Snail signaling pathway,which is a promising target for breast cancer metastasis therapy.
文摘BACKGROUND Gastrointestinal metastasis of breast cancer is rare,and clinicians may not have previously encountered this disease in clinical practice.CASE SUMMARY We report a patient with invasive lobular carcinoma of the breast who developed gastrointestinal metastasis two years after modified radical surgery.Mild elevation of carbohydrate antigen 15-3 was observed in the patient at an early stage;however,diagnosis and treatment were delayed due to non-specific clinical manifestations and no identifiable metastasis observed on imaging.CONCLUSION Clinicians should pay attention to gastrointestinal metastasis of breast cancer,especially invasive lobular carcinoma of the breast.
文摘Epithelial-mesenchymal transition (EMT) is a plastic and reversible process, essential for development and tissue homeostasis. Under pathological conditions, EMT causes induction of tumor growth, angiogenesis and metastasis. According to its reversible nature, the EMT program is associated with vast epigenetic changes. Targeting the epigenetic network that controls the EMT pathway in disease progression is a novel promising strategy to fight cancer metastasis. The impact of alterations in histone methylation in cancer has led to the identification of histone methyltransferases and demethylases as promising novel targets for therapy. Specifically, the lysine specific demethylase 1 (LSD1, also known as KDM1A) plays a pivotal role in the regulation of EMT. Here we present an overview of the causative role of LSD1 in the EMT process, summarizing recent findings on its emerging functions in cell migration and invasion in breast cancer.
