Most breast cancers are hormone-receptor positive(HR+).However,more women eventually die from HR+breast cancer than from either HER2+or triple negative breast cancer.Endocrine therapies continue to be the mainstay of ...Most breast cancers are hormone-receptor positive(HR+).However,more women eventually die from HR+breast cancer than from either HER2+or triple negative breast cancer.Endocrine therapies continue to be the mainstay of treatment.In 40%of these cases,recurrences in early-stage disease and progression in the metastatic setting are largely a function of the development of endocrine resistance.A multitude of mediators and pathways have been associated with endocrine resistance in breast cancer including the mevalonate pathway,which is integral to cholesterol biosynthesis.The mevalonate pathway and the downstream activation of associated cytoplasmic pathways including PI3K-AKT-mTOR and RAS-MEK-ERK have been known to affect cancer cell proliferation,cell survival,cell invasion,and metastasis.These are important mechanisms leading to the inevitable development of endocrine resistance in HR+breast cancer.Statins are a class of drugs that inhibits HMG-CoA reductase,an enzyme in the mevalonate pathway that plays a central role in cholesterol production.In vitro and in vitro studies suggest that the role of statins in blocking the mevalonate pathway effectively disrupts downstream pathways involved in estrogen receptor expression and cellular processes such as cell survival,proliferation,stress,cell cycle,inhibition of apoptosis,and autophagy.Overcoming these key mechanisms heralds a role for statins in the prevention of endocrine resistance.展开更多
The translational research strategy of targeting estrogen receptorα(ERα)positive breast cancer and then using long term anti-hormone adjuvant therapy(5-10 years)has reduced recurrences and mortality.However,resistan...The translational research strategy of targeting estrogen receptorα(ERα)positive breast cancer and then using long term anti-hormone adjuvant therapy(5-10 years)has reduced recurrences and mortality.However,resistance continues to occur and improvements are required to build on the success of tamoxifen and aromatase inhibitors(AIs)established over the past 40 years.Further translational research has described the evolution of acquired resistance of breast cancer cell lines to long term estrogen deprivation that parallels clinical experience over years.Additionally,recent reports have identified mutations in the ERαobtained from the recurrences of AI treated patients.These mutations allow the ERαto activate without ligands and auto stimulate metastatic tumor growth.Furthermore,the new biology of estrogen-induced apoptosis in acquired resistant models in vitro and in vivo has been interrogated and applied to clinical trials.Inflammation and stress are emerging concepts occurring in the process of acquired resistance and estrogen-induced apoptosis with different mechanisms.In this review,we will present progress in the understanding of acquired resistance,focus on stress and inflammatory responses in the development of acquired resistance,and consider approaches to create new treatments to improve the treatment of breast cancer with endocrine resistance.展开更多
Objective:To study the mechanism of action of Yanghe Huayan Decoction on endocrine-resistant cells(MCF-7R/mTOR cells)with low expression of mTOR;Methods:CCK-8 assay and cell clone assay were used to detect cell prolif...Objective:To study the mechanism of action of Yanghe Huayan Decoction on endocrine-resistant cells(MCF-7R/mTOR cells)with low expression of mTOR;Methods:CCK-8 assay and cell clone assay were used to detect cell proliferation and clonal ability,and flow cytometry was used to detect cell apoptosis.The changes of cytokines in ER-PI3K/Akt/mTOR signaling pathway were analyzed by blot and QPCR.Results:Yanghe Huayan Decoction could significantly affect the proliferation(p<0.05)and cloning ability(p<0.05)of MCF-7R/mTOR cells,promote cell apoptosis(p<0.01),and downregulate the expression of ER,PI3K,AKT,mTOR and p-mTOR(p<0.05).Conclusion:Yanghe Huayan Decoction can regulate the ER-PI3K/Akt/mTOR signaling pathway with multiple targets,and the use of combined mTOR inhibitors can regulate the ER-PI3K/Akt/mTOR signaling pathway more significantly.展开更多
Endocrine therapy(ET)is the therapy backbone of hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negati ve advanced breast cancer.However,there are about 20%HR positive patients with no...Endocrine therapy(ET)is the therapy backbone of hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negati ve advanced breast cancer.However,there are about 20%HR positive patients with no response to ET due to primary or acquired ET resistance.In this background,many agents have been studied to overcome ET resistance and of which the important agents are cyclin-dependent kinase 4/6(CDK4/6)inhibitors.The prognosis of advanced breast cancer has been improved by combing ET with CDK4/6 inhibitors.In this review,we mainly focused on the CDK4/6 inhibitors in the treatment of HR-positive,HER2-negative advanced breast cancer and discussed the action mechanisms of CDK4/6 inhibitors alone or combined with ET.We also summarized several molecular features that would predict response or resistance to CDK4/6 inhibitors.In addition,we put forward possible strategies to overcome CDK4/6 inhibitor resistance according to the latest research.展开更多
Nearly 70%of breast cancer(BC)is hormone-receptor(HR)-positive,human epidermal growth factor receptor 2(HER2)-negative,and endocrine therapy is the mainstay of treatment for this subtype.However,intrinsic or acquired ...Nearly 70%of breast cancer(BC)is hormone-receptor(HR)-positive,human epidermal growth factor receptor 2(HER2)-negative,and endocrine therapy is the mainstay of treatment for this subtype.However,intrinsic or acquired endocrine resistance can occur during the endocrine treatment.Based on insights of endocrine resistance mechanisms,a number of targeted therapies have been and continue to be developed.With regard to HR-positive,HER2-negative advanced BC,aromatase inhibitor(AI)is superior to tamoxifen,and fulvestrant is a better option for patients previously exposed to endocrine therapy.Targeted drugs,such as cyclindependent kinases(CDK)4/6 inhibitors,mammalian target of rapamycin(mTOR)inhibitors,phosphoinositide-3-kinase(PI3K)inhibitors,and histone deacetylase(HDAC)inhibitors,play a significant role in the present and show a promising future.With the application of CDK4/6 inhibitors becoming common,mechanisms of acquired resistance to them should also be taken into consideration.展开更多
Breast cancer,one of the most frequent cancer types,is a leading cause of death in women worldwide.Estrogen receptor(ER)αis a nuclear hormone receptor that plays key roles in mammary gland development and breast canc...Breast cancer,one of the most frequent cancer types,is a leading cause of death in women worldwide.Estrogen receptor(ER)αis a nuclear hormone receptor that plays key roles in mammary gland development and breast cancer.About 75%of breast cancer cases are diagnosed as ER-positive;however,nearly half of these cancers are either intrinsically or inherently resistant to the current anti-estrogen therapies.Recent studies have identified an ER coactivator,Mediator Subunit 1(MED1),as a unique,tissue-specific cofactor that mediates breast cancer metastasis and treatment resistance.MED1 is overexpressed in over 50%of human breast cancer cases and co-amplifies with another important breast cancer gene,receptor tyrosine kinase HER2.Clinically,MED1 expression highly correlates with poor disease-free survival of breast cancer patients,and recent studies have reported an increased frequency of MED1 mutations in the circulating tumor cells of patients after treatment.In this review,we discuss the biochemical characterization of MED1 and its associated MED1/Mediator complex,its crosstalk with HER2 in anti-estrogen resistance,breast cancer stem cell formation,and metastasis both in vitro and in vivo.Furthermore,we elaborate on the current advancements in targeting MED1 using state-of-the-art RNA nanotechnology and discuss the future perspectives as well.展开更多
Androgen deprivation therapy(ADT)is the mainstay regimen in patients with androgen-dependent prostate cancer(PCa).However,the selection of androgen-independent cancer cells leads to castrate resistant prostate cancer(...Androgen deprivation therapy(ADT)is the mainstay regimen in patients with androgen-dependent prostate cancer(PCa).However,the selection of androgen-independent cancer cells leads to castrate resistant prostate cancer(CRPC).The aggressive phenotype of CRPC cells underscores the need to elucidate mechanisms and therapeutic strategies to suppress CRPC outgrowth.Despite ADT,the activation of androgen receptor(AR)transcription factor continues via crosstalk with parallel signaling pathways.Understanding of how these signaling cascades are initiated and amplified post-ADT is lacking.Hormone deprivation can increase oxidative stress and the resultant reactive oxygen species(ROS)may activate both AR and non-AR signaling.Moreover,ROS-induced inflammatory cytokines may further amplify these redox signaling pathways to augment AR function.However,clinical trials using ROS quenching small molecule antioxidants have not suppressed CRPC progression,suggesting that more potent and persistent suppression of redox signaling in CRPC cells will be needed.The transcription factor Nrf2 increases the expression of numerous antioxidant enzymes and downregulates the function of inflammatory transcription factors,e.g.,nuclear factor kappa B.We documented that Nrf2 overexpression can suppress AR-mediated transcription in CRPC cell lines.Furthermore,two Nrf2 activating agents,sulforaphane(a phytochemical)and bardoxolone-methyl(a drug in clinical trial)suppress AR levels and sensitize CRPC cells to anti-androgens.These observations implicate the benefits of potent Nrf2-activators to suppress the lethal signaling cascades that lead to CRPC outgrowth.This review article will address the redox signaling networks that augment AR signaling during PCa progression to CRPC,and the possible utility of Nrf2-activating agents as an adjunct to ADT.展开更多
Endocrine therapy is essential for the treatment of patients with estrogen receptor positive (ER+) breast cancer, however, resistance and the development of metastatic disease is common. Understanding how ER+ breast c...Endocrine therapy is essential for the treatment of patients with estrogen receptor positive (ER+) breast cancer, however, resistance and the development of metastatic disease is common. Understanding how ER+ breast cancer metastasizes is critical since the major cause of death in breast cancer is metastasis to distant organs. Results from many studies suggest dysregulation of the estrogen receptor alpha gene (ESR1) contributes to therapeutic resistance and metastatic biology. This review covers both pre-clinical and clinical evidence on the spectrum ofESR1 alterations including amplification, point mutations, and genomic rearrangement events driving treatment resistance and metastatic potential of ER+ breast cancer. Importantly, we describe how these ESR1 alterations may provide therapeutic opportunities to improve outcomes in patients with lethal, metastatic breast cancer.展开更多
文摘Most breast cancers are hormone-receptor positive(HR+).However,more women eventually die from HR+breast cancer than from either HER2+or triple negative breast cancer.Endocrine therapies continue to be the mainstay of treatment.In 40%of these cases,recurrences in early-stage disease and progression in the metastatic setting are largely a function of the development of endocrine resistance.A multitude of mediators and pathways have been associated with endocrine resistance in breast cancer including the mevalonate pathway,which is integral to cholesterol biosynthesis.The mevalonate pathway and the downstream activation of associated cytoplasmic pathways including PI3K-AKT-mTOR and RAS-MEK-ERK have been known to affect cancer cell proliferation,cell survival,cell invasion,and metastasis.These are important mechanisms leading to the inevitable development of endocrine resistance in HR+breast cancer.Statins are a class of drugs that inhibits HMG-CoA reductase,an enzyme in the mevalonate pathway that plays a central role in cholesterol production.In vitro and in vitro studies suggest that the role of statins in blocking the mevalonate pathway effectively disrupts downstream pathways involved in estrogen receptor expression and cellular processes such as cell survival,proliferation,stress,cell cycle,inhibition of apoptosis,and autophagy.Overcoming these key mechanisms heralds a role for statins in the prevention of endocrine resistance.
基金This work was supported by the NIH/NCI(P30-CA016672)(Peter Pisters)Susan G.Komen for the Cure Foundation(SAC100009)to Jordan VC+2 种基金Cancer Prevention Research Institute of Texas(CPRIT)for the STARs and STARs plus Awards to Jordan VCthe George and Barbara Bush Foundation for Innovative Cancer Research to Jordan VCthe benefactors of the Dallas/Fort Worth Living Legend Chair of Cancer Research to Jordan VC.
文摘The translational research strategy of targeting estrogen receptorα(ERα)positive breast cancer and then using long term anti-hormone adjuvant therapy(5-10 years)has reduced recurrences and mortality.However,resistance continues to occur and improvements are required to build on the success of tamoxifen and aromatase inhibitors(AIs)established over the past 40 years.Further translational research has described the evolution of acquired resistance of breast cancer cell lines to long term estrogen deprivation that parallels clinical experience over years.Additionally,recent reports have identified mutations in the ERαobtained from the recurrences of AI treated patients.These mutations allow the ERαto activate without ligands and auto stimulate metastatic tumor growth.Furthermore,the new biology of estrogen-induced apoptosis in acquired resistant models in vitro and in vivo has been interrogated and applied to clinical trials.Inflammation and stress are emerging concepts occurring in the process of acquired resistance and estrogen-induced apoptosis with different mechanisms.In this review,we will present progress in the understanding of acquired resistance,focus on stress and inflammatory responses in the development of acquired resistance,and consider approaches to create new treatments to improve the treatment of breast cancer with endocrine resistance.
基金National Natural Science Foundation of China(No.81573989)
文摘Objective:To study the mechanism of action of Yanghe Huayan Decoction on endocrine-resistant cells(MCF-7R/mTOR cells)with low expression of mTOR;Methods:CCK-8 assay and cell clone assay were used to detect cell proliferation and clonal ability,and flow cytometry was used to detect cell apoptosis.The changes of cytokines in ER-PI3K/Akt/mTOR signaling pathway were analyzed by blot and QPCR.Results:Yanghe Huayan Decoction could significantly affect the proliferation(p<0.05)and cloning ability(p<0.05)of MCF-7R/mTOR cells,promote cell apoptosis(p<0.01),and downregulate the expression of ER,PI3K,AKT,mTOR and p-mTOR(p<0.05).Conclusion:Yanghe Huayan Decoction can regulate the ER-PI3K/Akt/mTOR signaling pathway with multiple targets,and the use of combined mTOR inhibitors can regulate the ER-PI3K/Akt/mTOR signaling pathway more significantly.
文摘Endocrine therapy(ET)is the therapy backbone of hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negati ve advanced breast cancer.However,there are about 20%HR positive patients with no response to ET due to primary or acquired ET resistance.In this background,many agents have been studied to overcome ET resistance and of which the important agents are cyclin-dependent kinase 4/6(CDK4/6)inhibitors.The prognosis of advanced breast cancer has been improved by combing ET with CDK4/6 inhibitors.In this review,we mainly focused on the CDK4/6 inhibitors in the treatment of HR-positive,HER2-negative advanced breast cancer and discussed the action mechanisms of CDK4/6 inhibitors alone or combined with ET.We also summarized several molecular features that would predict response or resistance to CDK4/6 inhibitors.In addition,we put forward possible strategies to overcome CDK4/6 inhibitor resistance according to the latest research.
文摘Nearly 70%of breast cancer(BC)is hormone-receptor(HR)-positive,human epidermal growth factor receptor 2(HER2)-negative,and endocrine therapy is the mainstay of treatment for this subtype.However,intrinsic or acquired endocrine resistance can occur during the endocrine treatment.Based on insights of endocrine resistance mechanisms,a number of targeted therapies have been and continue to be developed.With regard to HR-positive,HER2-negative advanced BC,aromatase inhibitor(AI)is superior to tamoxifen,and fulvestrant is a better option for patients previously exposed to endocrine therapy.Targeted drugs,such as cyclindependent kinases(CDK)4/6 inhibitors,mammalian target of rapamycin(mTOR)inhibitors,phosphoinositide-3-kinase(PI3K)inhibitors,and histone deacetylase(HDAC)inhibitors,play a significant role in the present and show a promising future.With the application of CDK4/6 inhibitors becoming common,mechanisms of acquired resistance to them should also be taken into consideration.
基金Project supported by the National Cancer Institute(No.R01CA197865),the Ride Cincinnati Awardthe National Center for Advancing Translation Science of the National Institutes of Health(No.UL1TR001425),USA
文摘Breast cancer,one of the most frequent cancer types,is a leading cause of death in women worldwide.Estrogen receptor(ER)αis a nuclear hormone receptor that plays key roles in mammary gland development and breast cancer.About 75%of breast cancer cases are diagnosed as ER-positive;however,nearly half of these cancers are either intrinsically or inherently resistant to the current anti-estrogen therapies.Recent studies have identified an ER coactivator,Mediator Subunit 1(MED1),as a unique,tissue-specific cofactor that mediates breast cancer metastasis and treatment resistance.MED1 is overexpressed in over 50%of human breast cancer cases and co-amplifies with another important breast cancer gene,receptor tyrosine kinase HER2.Clinically,MED1 expression highly correlates with poor disease-free survival of breast cancer patients,and recent studies have reported an increased frequency of MED1 mutations in the circulating tumor cells of patients after treatment.In this review,we discuss the biochemical characterization of MED1 and its associated MED1/Mediator complex,its crosstalk with HER2 in anti-estrogen resistance,breast cancer stem cell formation,and metastasis both in vitro and in vivo.Furthermore,we elaborate on the current advancements in targeting MED1 using state-of-the-art RNA nanotechnology and discuss the future perspectives as well.
基金supported by an intramural research grant from(LMU-DCOM)to Mondal D and Quadri SSA.
文摘Androgen deprivation therapy(ADT)is the mainstay regimen in patients with androgen-dependent prostate cancer(PCa).However,the selection of androgen-independent cancer cells leads to castrate resistant prostate cancer(CRPC).The aggressive phenotype of CRPC cells underscores the need to elucidate mechanisms and therapeutic strategies to suppress CRPC outgrowth.Despite ADT,the activation of androgen receptor(AR)transcription factor continues via crosstalk with parallel signaling pathways.Understanding of how these signaling cascades are initiated and amplified post-ADT is lacking.Hormone deprivation can increase oxidative stress and the resultant reactive oxygen species(ROS)may activate both AR and non-AR signaling.Moreover,ROS-induced inflammatory cytokines may further amplify these redox signaling pathways to augment AR function.However,clinical trials using ROS quenching small molecule antioxidants have not suppressed CRPC progression,suggesting that more potent and persistent suppression of redox signaling in CRPC cells will be needed.The transcription factor Nrf2 increases the expression of numerous antioxidant enzymes and downregulates the function of inflammatory transcription factors,e.g.,nuclear factor kappa B.We documented that Nrf2 overexpression can suppress AR-mediated transcription in CRPC cell lines.Furthermore,two Nrf2 activating agents,sulforaphane(a phytochemical)and bardoxolone-methyl(a drug in clinical trial)suppress AR levels and sensitize CRPC cells to anti-androgens.These observations implicate the benefits of potent Nrf2-activators to suppress the lethal signaling cascades that lead to CRPC outgrowth.This review article will address the redox signaling networks that augment AR signaling during PCa progression to CRPC,and the possible utility of Nrf2-activating agents as an adjunct to ADT.
基金a Susan G.Komen Promise Grant(PG12220321)to Ellis MJa Cancer Prevention Institute of Texas(CPRIT)Recruitment of Established Investigators Award(RR140033)to Ellis MJ+1 种基金a Breast Cancer Research Foundation Grant(BCRF ELFF-16-003)to Ellis MJby a National Institutes of Health Training Grant(T32-GM088129)to Lei JT
文摘Endocrine therapy is essential for the treatment of patients with estrogen receptor positive (ER+) breast cancer, however, resistance and the development of metastatic disease is common. Understanding how ER+ breast cancer metastasizes is critical since the major cause of death in breast cancer is metastasis to distant organs. Results from many studies suggest dysregulation of the estrogen receptor alpha gene (ESR1) contributes to therapeutic resistance and metastatic biology. This review covers both pre-clinical and clinical evidence on the spectrum ofESR1 alterations including amplification, point mutations, and genomic rearrangement events driving treatment resistance and metastatic potential of ER+ breast cancer. Importantly, we describe how these ESR1 alterations may provide therapeutic opportunities to improve outcomes in patients with lethal, metastatic breast cancer.