Objectives:Tamoxifen is a key drug that provides endocrine therapy for estrogen receptor(ER)α-positive breast cancer;however,resistance remains a significant clinical challenge.This study aims to investigate the mole...Objectives:Tamoxifen is a key drug that provides endocrine therapy for estrogen receptor(ER)α-positive breast cancer;however,resistance remains a significant clinical challenge.This study aims to investigate the molecular mechanisms of tamoxifen resistance in ERα-positive breast cancer,with particular focus on the role of SET Domain Containing 1A(SETD1A)-driven forkhead box A2(FOXA2)as a key regulator of this resistance.Methods:FOXA2 expression and its regulation by SETD1A were assessed via(quantitative polymerase chain reaction),western blotting,transcriptome profiling,and chromatin immunoprecipitation analyses.The effects of FOXA2 on cell proliferation,migration,invasion,and cancer stem cell traits were evaluated using small interfering RNA(siRNA)-mediated silencing.Clinical relevance was examined by analyzing patient datasets and tumor tissue microarrays.Results:FOXA2 expression was significantly elevated in tamoxifen-resistant(TamR)and ERα-negative breast cancer cells compared to that in ERα-positive MCF-7 cells,regardless of tamoxifen treatment or ERαdepletion.Transcriptome and chromatin immunoprecipitation analyses revealed that SETD1A,a histone methyltransferase,directly regulated FOXA2 expression.Functionally,FOXA2 knockdown inhibited the proliferation,migration,invasion,and cancer stem cell properties of TamR cells while restoring tamoxifen sensitivity.High FOXA2 expression was correlated with poor survival and reduced responsiveness to tamoxifen in patients with ER-positive breast cancer.Conclusion:Our findings identified FOXA2 as a key mediator of tamoxifen resistance regulated by SETD1A and suggested that targeting the SETD1A-FOXA2 axis may offer a novel strategy for overcoming endocrine resistance in breast cancer.展开更多
Objective Selective estrogen receptor modulators(SERMs)have demonstrated efficacy in the treatment of hypogonadism in males and male factor infertility.Two SERMs,clomiphene citrate and tamoxifen,are now prescribed for...Objective Selective estrogen receptor modulators(SERMs)have demonstrated efficacy in the treatment of hypogonadism in males and male factor infertility.Two SERMs,clomiphene citrate and tamoxifen,are now prescribed for off-label use to treat both conditions in males.However,existing literature compares mixed protocols with active management.We aimed to conduct a meta-analysis to evaluate the effect of clomiphene and tamoxifen versus placebo on natural pregnancy rates.Methods We conducted a comprehensive systematic review of electronic databases:MEDLINE,PubMed/PMC,EMBASE,CINAHL,Cochrane Central Register of Controlled Trials(CENTRAL),Scopus,Google Scholar,and Web of Science.Articles satisfying all selection criteria were analyzed.The primary outcome was the incidence of pregnancy after receiving the treatment.Secondary outcomes included serum follicle-stimulating hormone,luteinizing hormone,and testosterone levels,and sperm count and motility.We calculated the pooled odds ratio,risk ratio,and risk difference to ascertain possible alterations in the direction of the pooled effect size.Results Ten randomized controlled trials were ultimately included and underwent data extraction.Clomiphene citrate and placebo groups had similar pregnancy rates(10.4%and 7.1%,respectively;odds ratio 1.30[95%confidence interval 0.27–6.17];p=0.74).No meta-analysis could be calculated for pregnancy rates in tamoxifen versus placebo groups.Heterogeneity among the studies of both SERMs ranged from low to high.Conclusion Although clomiphene citrate and tamoxifen are often used off-label for the treatment of male infertility secondary to hypogonadism,studies of SERMs in the treatment of idiopathic male factor infertility are limited and heterogenous,preventing this meta-analysis from investigating the efficacy of SERMs on male infertility.The effect of clomiphene citrate or tamoxifen on the pregnancy rate remains uncertain.展开更多
BACKGROUND Tamoxifen,a selective estrogen receptor modulator,is pivotal in managing hor-mone receptor-positive breast cancer.While its common side effects are well-do-cumented,tamoxifen-induced thrombocytopenia is a r...BACKGROUND Tamoxifen,a selective estrogen receptor modulator,is pivotal in managing hor-mone receptor-positive breast cancer.While its common side effects are well-do-cumented,tamoxifen-induced thrombocytopenia is a rare,serious adverse event requiring drug discontinuation.CASE SUMMARY We report a case of tamoxifen-induced thrombocytopenia in a 51-year-old preme-nopausal woman with breast cancer,occurring within 4 weeks of initiating adju-vant tamoxifen therapy.Platelet counts normalized after drug cessation,but th-rombocytopenia recurred upon rechallenge,leading to permanent disconti-nuation.CONCLUSION This case underscores the need for regular complete blood count monitoring in patients on tamoxifen to detect rare hematologic adverse events promptly.展开更多
The side effects of tamoxifen are generally mild, including the effect on lipoprotein metabolism. However, there are few cases of severe tamoxifen induced hypertriglyceridemia. Hypertriglyceridemia is a marked risk fa...The side effects of tamoxifen are generally mild, including the effect on lipoprotein metabolism. However, there are few cases of severe tamoxifen induced hypertriglyceridemia. Hypertriglyceridemia is a marked risk factor for acute pancreatitis and approximately 2% to 5% of cases of acute pancreatitis are related to drugs. We report on tamoxifen-induced hypertriglyceridemia and acute pancreatitis in a 40 years old woman with type 2 diabetes mellitus occurred by dexamethasone. She was treated with insulin infusion and fenofibrate, and goserelin acetate was started instead of tamoxifen after discharge from the hospital. Also, probable pathogenic hypotheses about the correlation between tamoxifen and dexamethasone induced type 2 diabetes mellitus on severe acute pancreatitis are provided. Clinicians should take care of risks of severe acute pancreatitis on using tamoxifen, especially for patients with dexamethasone induced diabetes mellitus. These individuals should undergo pre-post tamoxifen lipid screening and careful history taking of drugs, including dexamethasone.展开更多
It was reported previously that tamoxifen （TAM） could increase the intracellular accumulation of drug-loaded liposomes, but the exact mechanism is unknown although it was supposed that TAM might enhance the cell upt...It was reported previously that tamoxifen （TAM） could increase the intracellular accumulation of drug-loaded liposomes, but the exact mechanism is unknown although it was supposed that TAM might enhance the cell uptake by inhibiting the drug efflux caused by P-glycoprotein （P-gp）. To identify the mechanism of increased cellular uptake of liposomes induced by tamoxifen, PEGgylated liposomes （SSL） ofP-gp-substrate doxorubicin （DOX） or non-P-gp-substrate coumarin （Cou） were prepared with or without TAM. The cell uptake of these liposome systems was investigated in cell lines with different P-gp-expressing levels and the interaction of TAM with lipid membrane was also studied. As the results, the co-encapsulation of TAM with DOX-SSL increased the intracellular uptake in all three tumor cell lines. In P-gp-highly-expressing MCF-7/Adr cells, the effect of TAM was the strongest and in negative control Hela cells, the impact weakened but still significant. The improvement was also observed in the cellular uptake of Cou-SSL. Surface plasmon resonance （SPR） studies demonstrated that TAM-SSL exhibited a much stronger atYmity with model biomembrane compared with empty SSL, and ft^her test with isothermal titration calorimetry （ITC） showed that free TAM had an obvious interaction with lipid membrane. In conclusion, TAM could increase the affinity of liposomes with biomembrane and enhance the intracellular accumulation of liposomes via both TAM-mediated P-gp inhibition and the increased interaction between hydrophobic TAM molecules and lipid membrane.展开更多
Spinal cord injury （SCI） is a devastating condition that produces significant changes in the life- style of patients. Many molecular and cellular events are triggered after the initial physical impact to the cord. T...Spinal cord injury （SCI） is a devastating condition that produces significant changes in the life- style of patients. Many molecular and cellular events are triggered after the initial physical impact to the cord. Two major phases have been described in the field of SCI： an acute phase and late phase. Most of the therapeutic strategies are focused on the late phase because this provides an opportunity to target cellular events like apoptosis, demyelination, scar formation and axonal outgrowth. In this mini-review, we will focus on two agents （tamoxifen and a Src kinase family inhibitor known as PP2） that have been shown in our laboratory to produce neuroprotective （increase cell survival） and/or regenerative （axonal outgrowth） actions. The animal model used in our laboratory is adult female rat （N250 g） with a moderate contusion （12.5 mm） to the spinal cord at the T10 level, using the MASCIS impactor device. Tamoxifen or PP2 was administered by implantation of a 15 mg pellet （Innovative Research of America, Sarasota, FL, USA） or by intraperitoneal injections （1.5 mg/kg, every 3 days）, respectively, to produce a long-term effect （28 days）. Tamoxifen and the Src kinase inhibitor, PP2, are drugs that in rats with a moderate spinal cord injury promote functional locomotor recovery, increase spared white matter tissue, and stimulate axonal outgrowth. Moreover, tamoxifen reduces the formation of reactive oxygen species. Therefore, these drugs are possible therapeutic agents that have a neuroprotective/regen- erative activity in vertebrates with SCI.展开更多
基金supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF),funded by the Ministry of Education(RS-2023-00248378 and NRF-2020R1A6A1A03043708).
文摘Objectives:Tamoxifen is a key drug that provides endocrine therapy for estrogen receptor(ER)α-positive breast cancer;however,resistance remains a significant clinical challenge.This study aims to investigate the molecular mechanisms of tamoxifen resistance in ERα-positive breast cancer,with particular focus on the role of SET Domain Containing 1A(SETD1A)-driven forkhead box A2(FOXA2)as a key regulator of this resistance.Methods:FOXA2 expression and its regulation by SETD1A were assessed via(quantitative polymerase chain reaction),western blotting,transcriptome profiling,and chromatin immunoprecipitation analyses.The effects of FOXA2 on cell proliferation,migration,invasion,and cancer stem cell traits were evaluated using small interfering RNA(siRNA)-mediated silencing.Clinical relevance was examined by analyzing patient datasets and tumor tissue microarrays.Results:FOXA2 expression was significantly elevated in tamoxifen-resistant(TamR)and ERα-negative breast cancer cells compared to that in ERα-positive MCF-7 cells,regardless of tamoxifen treatment or ERαdepletion.Transcriptome and chromatin immunoprecipitation analyses revealed that SETD1A,a histone methyltransferase,directly regulated FOXA2 expression.Functionally,FOXA2 knockdown inhibited the proliferation,migration,invasion,and cancer stem cell properties of TamR cells while restoring tamoxifen sensitivity.High FOXA2 expression was correlated with poor survival and reduced responsiveness to tamoxifen in patients with ER-positive breast cancer.Conclusion:Our findings identified FOXA2 as a key mediator of tamoxifen resistance regulated by SETD1A and suggested that targeting the SETD1A-FOXA2 axis may offer a novel strategy for overcoming endocrine resistance in breast cancer.
文摘Objective Selective estrogen receptor modulators(SERMs)have demonstrated efficacy in the treatment of hypogonadism in males and male factor infertility.Two SERMs,clomiphene citrate and tamoxifen,are now prescribed for off-label use to treat both conditions in males.However,existing literature compares mixed protocols with active management.We aimed to conduct a meta-analysis to evaluate the effect of clomiphene and tamoxifen versus placebo on natural pregnancy rates.Methods We conducted a comprehensive systematic review of electronic databases:MEDLINE,PubMed/PMC,EMBASE,CINAHL,Cochrane Central Register of Controlled Trials(CENTRAL),Scopus,Google Scholar,and Web of Science.Articles satisfying all selection criteria were analyzed.The primary outcome was the incidence of pregnancy after receiving the treatment.Secondary outcomes included serum follicle-stimulating hormone,luteinizing hormone,and testosterone levels,and sperm count and motility.We calculated the pooled odds ratio,risk ratio,and risk difference to ascertain possible alterations in the direction of the pooled effect size.Results Ten randomized controlled trials were ultimately included and underwent data extraction.Clomiphene citrate and placebo groups had similar pregnancy rates(10.4%and 7.1%,respectively;odds ratio 1.30[95%confidence interval 0.27–6.17];p=0.74).No meta-analysis could be calculated for pregnancy rates in tamoxifen versus placebo groups.Heterogeneity among the studies of both SERMs ranged from low to high.Conclusion Although clomiphene citrate and tamoxifen are often used off-label for the treatment of male infertility secondary to hypogonadism,studies of SERMs in the treatment of idiopathic male factor infertility are limited and heterogenous,preventing this meta-analysis from investigating the efficacy of SERMs on male infertility.The effect of clomiphene citrate or tamoxifen on the pregnancy rate remains uncertain.
文摘BACKGROUND Tamoxifen,a selective estrogen receptor modulator,is pivotal in managing hor-mone receptor-positive breast cancer.While its common side effects are well-do-cumented,tamoxifen-induced thrombocytopenia is a rare,serious adverse event requiring drug discontinuation.CASE SUMMARY We report a case of tamoxifen-induced thrombocytopenia in a 51-year-old preme-nopausal woman with breast cancer,occurring within 4 weeks of initiating adju-vant tamoxifen therapy.Platelet counts normalized after drug cessation,but th-rombocytopenia recurred upon rechallenge,leading to permanent disconti-nuation.CONCLUSION This case underscores the need for regular complete blood count monitoring in patients on tamoxifen to detect rare hematologic adverse events promptly.
文摘The side effects of tamoxifen are generally mild, including the effect on lipoprotein metabolism. However, there are few cases of severe tamoxifen induced hypertriglyceridemia. Hypertriglyceridemia is a marked risk factor for acute pancreatitis and approximately 2% to 5% of cases of acute pancreatitis are related to drugs. We report on tamoxifen-induced hypertriglyceridemia and acute pancreatitis in a 40 years old woman with type 2 diabetes mellitus occurred by dexamethasone. She was treated with insulin infusion and fenofibrate, and goserelin acetate was started instead of tamoxifen after discharge from the hospital. Also, probable pathogenic hypotheses about the correlation between tamoxifen and dexamethasone induced type 2 diabetes mellitus on severe acute pancreatitis are provided. Clinicians should take care of risks of severe acute pancreatitis on using tamoxifen, especially for patients with dexamethasone induced diabetes mellitus. These individuals should undergo pre-post tamoxifen lipid screening and careful history taking of drugs, including dexamethasone.
基金National Natural Science Foundation of China(Grant No.81130059)
文摘It was reported previously that tamoxifen （TAM） could increase the intracellular accumulation of drug-loaded liposomes, but the exact mechanism is unknown although it was supposed that TAM might enhance the cell uptake by inhibiting the drug efflux caused by P-glycoprotein （P-gp）. To identify the mechanism of increased cellular uptake of liposomes induced by tamoxifen, PEGgylated liposomes （SSL） ofP-gp-substrate doxorubicin （DOX） or non-P-gp-substrate coumarin （Cou） were prepared with or without TAM. The cell uptake of these liposome systems was investigated in cell lines with different P-gp-expressing levels and the interaction of TAM with lipid membrane was also studied. As the results, the co-encapsulation of TAM with DOX-SSL increased the intracellular uptake in all three tumor cell lines. In P-gp-highly-expressing MCF-7/Adr cells, the effect of TAM was the strongest and in negative control Hela cells, the impact weakened but still significant. The improvement was also observed in the cellular uptake of Cou-SSL. Surface plasmon resonance （SPR） studies demonstrated that TAM-SSL exhibited a much stronger atYmity with model biomembrane compared with empty SSL, and ft^her test with isothermal titration calorimetry （ITC） showed that free TAM had an obvious interaction with lipid membrane. In conclusion, TAM could increase the affinity of liposomes with biomembrane and enhance the intracellular accumulation of liposomes via both TAM-mediated P-gp inhibition and the increased interaction between hydrophobic TAM molecules and lipid membrane.
基金partially supported by the MBRS-RISE Program(R25 GM061838)COBRE(5P20-GM103642)
文摘Spinal cord injury （SCI） is a devastating condition that produces significant changes in the life- style of patients. Many molecular and cellular events are triggered after the initial physical impact to the cord. Two major phases have been described in the field of SCI： an acute phase and late phase. Most of the therapeutic strategies are focused on the late phase because this provides an opportunity to target cellular events like apoptosis, demyelination, scar formation and axonal outgrowth. In this mini-review, we will focus on two agents （tamoxifen and a Src kinase family inhibitor known as PP2） that have been shown in our laboratory to produce neuroprotective （increase cell survival） and/or regenerative （axonal outgrowth） actions. The animal model used in our laboratory is adult female rat （N250 g） with a moderate contusion （12.5 mm） to the spinal cord at the T10 level, using the MASCIS impactor device. Tamoxifen or PP2 was administered by implantation of a 15 mg pellet （Innovative Research of America, Sarasota, FL, USA） or by intraperitoneal injections （1.5 mg/kg, every 3 days）, respectively, to produce a long-term effect （28 days）. Tamoxifen and the Src kinase inhibitor, PP2, are drugs that in rats with a moderate spinal cord injury promote functional locomotor recovery, increase spared white matter tissue, and stimulate axonal outgrowth. Moreover, tamoxifen reduces the formation of reactive oxygen species. Therefore, these drugs are possible therapeutic agents that have a neuroprotective/regen- erative activity in vertebrates with SCI.
