OBJECTIVE TNF-related apoptosis-inducing ligand(TRAIL)is a promising cancer therapeutic agent due to its minimal toxicity to normal tissues and remarkable apoptotic activity in tumors.However,most breast cancer cells ...OBJECTIVE TNF-related apoptosis-inducing ligand(TRAIL)is a promising cancer therapeutic agent due to its minimal toxicity to normal tissues and remarkable apoptotic activity in tumors.However,most breast cancer cells are resistant to TRAIL-induced apoptosis.Our objectives are to investigate the underlying molecular mechanisms and to develop strategies to overcome such resistance.METHODS To identify modulators of TRAIL-induced apoptosis,we carried out a genome wide si RNA screen.To validate the screening result,we either silenced or overexpressed the identified genes in various breast cancer cells and changes in growth and TRAIL-induced cell apoptosis were determined in vitro and in an orthotopic xenograft mouse model.Finally,we investigated whether small molecules targeting the identified genes improve the effectiveness of TRAIL-therapy.RESULTS We unexpectedly identified androgen receptor(AR)to be responsible for TRAIL resistance.While AR is classically viewed as the key factor in prostate cancer progression,we found that AR expression levels were markedly elevated in human invasive breast cancer specimens including triple-negative breast cancers(TNBC)that are highly aggressive with poor prognosis.Importantly,breast cancer cell lines express different levels of AR that correlated with their TRAIL resistance.AR overexpression in MDA-MB-231 and MDA-MB-436 cells suppressed the TRAIL sensitivity whereas knockdown of AR rendered MCF-7 and MDA-MB-453 cells sensitive to TRAIL-induced apoptosis.AR overexpression also induced TRAIL resistance in breast tumors in vivo.Further,we observed an upregulation of the TRAIL receptor,death receptor 5(DR5)in breast cancer cells,following the removal or inhibition of AR by its antagonists Casodex and MDV3100.Treatment with AR antagonists also enhanced TRAIL-induced breast cancer cell apoptosis.CONCLUSION AR signaling suppresses TRAIL-induced breast cancer cell apoptosis,in part,by suppressing DR5 expression,and a combination of AR antagonists together with TRAIL may be a novel and effective therapy for TNBC.展开更多
Androgen deprivation therapy(ADT)with gonadotropin-releasing hormone(GnRH)agonists and antagonists is the mainstay of advanced prostate cancer treatment.Both drug classes decrease levels of luteinizing hormone and fol...Androgen deprivation therapy(ADT)with gonadotropin-releasing hormone(GnRH)agonists and antagonists is the mainstay of advanced prostate cancer treatment.Both drug classes decrease levels of luteinizing hormone and follicle-stimulating hormones(FSH),thereby lowering testosterone to castrate levels.This is associated with adverse events(AEs),including cardiovascular(CV)disorders,bone fractures,metabolic dysfunction,and impaired cognitive function.This literature review discusses these AEs,with a focus on CV and bone-related events.A hypothesis-generating meta-analysis of six clinical trials showed a potentially increased risk for CV disorders with GnRH agonists versus the GnRH antagonist degarelix.While no study has directly compared GnRH agonists versus antagonists with a primary CV outcome,one hypothesis for this observation is that GnRH agonists lead to initial surges in FSH that may negatively impact CV health,whereas antagonists do not.GnRH agonists are associated with metabolic and cognitive AEs and while data are lacking for GnRH antagonists,no differences in risk are predicted.Other common AEs with ADT include injection site reactions,which are much more common with degarelix than with GnRH agonists,which may reflect differing administration and injection techniques.Future studies are needed to further evaluate and compare the safety profiles of GnRH agonists and antagonists,especially in patients with pre-existing CV disease and other co-morbidities.Physicians should carefully evaluate benefits and risks when prescribing ADT and ensure that side effects are well managed.展开更多
基金supported by National Institutes of Health(R21CA193271 and R01HL116849)National Natural Science Foundation of China(31100595 and 31300683)
文摘OBJECTIVE TNF-related apoptosis-inducing ligand(TRAIL)is a promising cancer therapeutic agent due to its minimal toxicity to normal tissues and remarkable apoptotic activity in tumors.However,most breast cancer cells are resistant to TRAIL-induced apoptosis.Our objectives are to investigate the underlying molecular mechanisms and to develop strategies to overcome such resistance.METHODS To identify modulators of TRAIL-induced apoptosis,we carried out a genome wide si RNA screen.To validate the screening result,we either silenced or overexpressed the identified genes in various breast cancer cells and changes in growth and TRAIL-induced cell apoptosis were determined in vitro and in an orthotopic xenograft mouse model.Finally,we investigated whether small molecules targeting the identified genes improve the effectiveness of TRAIL-therapy.RESULTS We unexpectedly identified androgen receptor(AR)to be responsible for TRAIL resistance.While AR is classically viewed as the key factor in prostate cancer progression,we found that AR expression levels were markedly elevated in human invasive breast cancer specimens including triple-negative breast cancers(TNBC)that are highly aggressive with poor prognosis.Importantly,breast cancer cell lines express different levels of AR that correlated with their TRAIL resistance.AR overexpression in MDA-MB-231 and MDA-MB-436 cells suppressed the TRAIL sensitivity whereas knockdown of AR rendered MCF-7 and MDA-MB-453 cells sensitive to TRAIL-induced apoptosis.AR overexpression also induced TRAIL resistance in breast tumors in vivo.Further,we observed an upregulation of the TRAIL receptor,death receptor 5(DR5)in breast cancer cells,following the removal or inhibition of AR by its antagonists Casodex and MDV3100.Treatment with AR antagonists also enhanced TRAIL-induced breast cancer cell apoptosis.CONCLUSION AR signaling suppresses TRAIL-induced breast cancer cell apoptosis,in part,by suppressing DR5 expression,and a combination of AR antagonists together with TRAIL may be a novel and effective therapy for TNBC.
文摘Androgen deprivation therapy(ADT)with gonadotropin-releasing hormone(GnRH)agonists and antagonists is the mainstay of advanced prostate cancer treatment.Both drug classes decrease levels of luteinizing hormone and follicle-stimulating hormones(FSH),thereby lowering testosterone to castrate levels.This is associated with adverse events(AEs),including cardiovascular(CV)disorders,bone fractures,metabolic dysfunction,and impaired cognitive function.This literature review discusses these AEs,with a focus on CV and bone-related events.A hypothesis-generating meta-analysis of six clinical trials showed a potentially increased risk for CV disorders with GnRH agonists versus the GnRH antagonist degarelix.While no study has directly compared GnRH agonists versus antagonists with a primary CV outcome,one hypothesis for this observation is that GnRH agonists lead to initial surges in FSH that may negatively impact CV health,whereas antagonists do not.GnRH agonists are associated with metabolic and cognitive AEs and while data are lacking for GnRH antagonists,no differences in risk are predicted.Other common AEs with ADT include injection site reactions,which are much more common with degarelix than with GnRH agonists,which may reflect differing administration and injection techniques.Future studies are needed to further evaluate and compare the safety profiles of GnRH agonists and antagonists,especially in patients with pre-existing CV disease and other co-morbidities.Physicians should carefully evaluate benefits and risks when prescribing ADT and ensure that side effects are well managed.
