Randomized phase II trial of preoperative fulvestrant with or without enzalutamide for ER+/Her2- primary breast cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE271080 | GEO | 2024/06/30
REPOSITORIES: GEO
Similar Datasets
Project description:In this study, we found the efficacy of AR-targeting drugs largely depended on the context of AR (Androgen Receptor) and ERα (Estrogen Receptor) status. Enzalutamide, an AR blocker, had a better inhibition effect on ER+ cells with lower AR expressed compared to cells expressed higher AR. To explore the mechanism of action of Enzalutamide, we performed ChIP-seq to illustrate the AR and ER genomic bindings after Enzalutamide treatment in both MCF7 and MCF7 with AR over expression (AROE) cells. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for androgen receptor (AR) and Estrogen receptor (ER) after Enzalutamide treatment in MCF7 and MCF7 AROE cells
2022-11-28 | GSE200300 | GEO
Project description:Estrogen receptor α (ER-α) is a major driver of breast cancer (BC), being expressed in 75% of all BC cases. Agents such as tamoxifen are used to block ER-α activity and interfere with its down-stream oncogenic singling. However, a major problem associated with tamoxifen is the emergence of resistance. Resistant BC is often associated with aggressive relapse, metastasis, and high mortality rates of 80%. A key mechanism for development of resistance is activation of EGFR/HER2/HER3 signaling pathways and other hormone receptors (androgen receptor (AR), progesterone receptor (PR), prolactin receptors (PRL-R)) that can intrinsically activate ER-α. This study investigated a novel class of thiosemicarbazone anti-cancer agents, namely Dp44mT and DpC, on the expression and activation between major BC hormonal receptors, their co-factors and key pathways involved in resistance in ER-α-positive BC using RNA sequencing, immunoblotting and confocal microscopy and an in vivo orthotopic BC model. For the first time, we demonstrate that DpC and Dp44mT markedly reduce the expression of ER-α, AR, PR and PRL-R by inducing their proteasomal degradation. Further, these agents also inhibited EGFR, HER2 and HER3 activation in ER-α-positive BC cells, suggesting their potential ability to overcome development of resistance. Importantly, expression of key co-factors that promote ER-α-transcriptional activity, including SRC3, c-Myc, SP1, and c-Src, were also decreased by these agents. This study demonstrates for the first time the multi-axial inhibitory effects of the novel DpT agents in ER-positive BC invitro and in vivo. We demonstrate that Dp44mT and DpC decrease ER-α expression, transcriptional activity, and promote its proteasomal degradation. This study also demonstrated the ability of the DpT agents in inhibiting RTKs and key oncogenic pathways that are well established to promote endocrine resistance. Hence, for the first time we demonstrate that Dp44mT and DpC may be a promising therapeutic approach to treat ER-positive BC and to overcome resistance to conventional BC therapies.
2023-02-28 | GSE192942 | GEO
Project description:Phosphoinositide-3-kinase/protein-kinaseB/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling plays an important role in breast cancer (BC). Its interaction with estrogen receptor (ER) signalling becomes more complex and inter-dependent with acquired endocrine resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility, however, a negative feedback-loop exists downstream of PI3K/AKT/mTOR. Direct blockade of AKT together with endocrine therapy may improve BC treatment. AZD5363, a novel pan-AKT kinase catalytic inhibitor, was examined in a panel of ER+ BC cell lines (MCF7, HCC1428, T47D, ZR75.1) adapted to long-term-estrogen-deprivation (LTED) or tamoxifen (TamR). AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50<500nM) except HCC1428 and HCC1428-LTED. T47D-LTED and ZR75-LTED were the most sensitive of the lines (GI50~100nM). AZD5363 re-sensitised TamR cells to tamoxifen and acted synergistically with fulvestrant. AZD5363 decreased p-AKT/mTOR targets leading to a reduction in ERα-mediated transcription in a context specific manner and concomitant decrease in recruitment of ER and CREB-binding protein (CBP) to estrogen-response-elements located on the TFF1, PGR and GREB1 promoters. Furthermore, AZD5363 reduced expression of cell-cycle-regulatory proteins. Global gene expression highlighted ERBB2-ERBB3, ERK5 and IGF1 signaling pathways driven by MYC as potential feedback-loops. Combined treatment with AZD5363 and fulvestrant showed synergy in an ER+ patient derived xenograft and delayed tumour progression post-cessation of therapy. These data support the combination of AZD5363 with fulvestrant as a potential therapy for BC that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response, supporting the need for clinical evaluation. Cell lines were treated in biological triplicates in the absence of estrogen with or without AZD5363 for 24hours in order to identify gene changes associated with perturbation of AKT signalling
2015-06-29 | E-GEOD-69893 | biostudies-arrayexpress
Project description:Background: Numerous studies have focused on the PI3K/AKT/mTOR pathway in estrogen receptor positive (ER) breast cancer (BC), as a linear signal transduction pathway and reported its association with worse clinical outcomes. To gain better insight into the relative contribution of each of the signalling pathways which lie downstream to PI3K (namely AKT and mTOR) to BC outcomes, we have developed a novel in silico approach which assessed the activation of each of these signalling pathways separately. Methods: By analysing gene expression and matched proteomic data in ER-positive patients from the TCGA repository, we developed gene signatures that reflect the level of expression of phosphorylated-Serine473-AKT (pAKT) and phosphorylated-Serine2448-mTOR (p-mTOR) separately, capturing their corresponding level of pathway activation. Using pooled analysis of gene-expression data from over 7,000 patients with ER-positive early BC, we then investigated the association between pathway activation and outcomes. Results: Our analysis revealed that the pAKT pathway activation (as measured by the developed signature) was associated with luminal A BC while the p-mTOR pathway activation was more associated with luminal B BC (Kruskal-Wallis test p<10-10). pAKT pathway activation was significantly associated with better outcomes (multivariable HR, 0.79; 95% CI, 0.74 to 0.85; p=2.5x10-10) whereas p-mTOR pathway activation showed worse outcomes (multivariable HR, 1.1; 95% CI, 1.1 to 1.2; p=9.9x10-4). Similar associations between activation and outcomes were obtained when the analysis was performed in patients who were treated with hormonal therapy. Additionally, pAKT pathway activation predicted better outcomes irrespective of the BC molecular subtypes (luminal A multivariable HR, 0.85; 95% CI, 0.75 to 0.96; p=0.01; luminal B HR, 0.91; 95% CI, 0.83 to 0.99; p=0.033). pAKT pathway activation was associated with PIK3CA mutations (p=0.0001) while p-mTOR pathway activation was associated with p53 mutations (p=0.04). Finally, we show that pAKT pathway activation was associated with less response to Everolimus. Conclusions: Our data show that pAKT and p-mTOR pathway activation have differing impact on prognosis and suggest that they are not linearly connected in luminal breast cancers. These findings add to our understanding of signalling through the PI3K pathway and could have important implications for the treatment of luminal BC.
2018-12-14 | GSE123832 | GEO
Project description:Phosphoinositide-3-kinase/protein-kinaseB/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling plays an important role in breast cancer (BC). Its interaction with estrogen receptor (ER) signalling becomes more complex and inter-dependent with acquired endocrine resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility, however, a negative feedback-loop exists downstream of PI3K/AKT/mTOR. Direct blockade of AKT together with endocrine therapy may improve BC treatment. AZD5363, a novel pan-AKT kinase catalytic inhibitor, was examined in a panel of ER+ BC cell lines (MCF7, HCC1428, T47D, ZR75.1) adapted to long-term-estrogen-deprivation (LTED) or tamoxifen (TamR). AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50<500nM) except HCC1428 and HCC1428-LTED. T47D-LTED and ZR75-LTED were the most sensitive of the lines (GI50~100nM). AZD5363 re-sensitised TamR cells to tamoxifen and acted synergistically with fulvestrant. AZD5363 decreased p-AKT/mTOR targets leading to a reduction in ERα-mediated transcription in a context specific manner and concomitant decrease in recruitment of ER and CREB-binding protein (CBP) to estrogen-response-elements located on the TFF1, PGR and GREB1 promoters. Furthermore, AZD5363 reduced expression of cell-cycle-regulatory proteins. Global gene expression highlighted ERBB2-ERBB3, ERK5 and IGF1 signaling pathways driven by MYC as potential feedback-loops. Combined treatment with AZD5363 and fulvestrant showed synergy in an ER+ patient derived xenograft and delayed tumour progression post-cessation of therapy. These data support the combination of AZD5363 with fulvestrant as a potential therapy for BC that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response, supporting the need for clinical evaluation.
2015-06-29 | GSE69893 | GEO
Project description:We carried out a comparative study of the orally bioavailable investigational SERD elacestrant, versus fulvestrant, in models of endocrine sensitive and resistant BC harbouring varying genetic backgrounds. Both drugs showed comparable effects on tumour growth of ER+ patient-derived xenograft models harbouring several ESR1 mutations and elacestrant showed activity after acquired resistance to fulvestrant. Treatment with either drug showed similar impact on ER-cistrome, ER- interactome and suppression of estrogen-regulated genes, confirming the anti-estrogenic activity of elacestrant.
2022-08-01 | GSE190384 | GEO
Project description:We carried out a comparative study of the orally bioavailable investigational SERD elacestrant, versus fulvestrant, in models of endocrine sensitive and resistant BC harbouring varying genetic backgrounds. Both drugs showed comparable effects on tumour growth of ER+ patient-derived xenograft models harbouring several ESR1 mutations and elacestrant showed activity after acquired resistance to fulvestrant. Treatment with either drug showed similar impact on ER-cistrome, ER- interactome and suppression of estrogen-regulated genes, confirming the anti-estrogenic activity of elacestrant.
2022-08-01 | GSE190385 | GEO
Project description:Estrogens have been shown to elicit anti-cancer effects against estrogen receptor alpha (ER)-positive breast cancer. We sought to determine the underlying mechanism of therapeutic response. Response to 17b-estradiol was assessed in ER+ breast cancer models with resistance to estrogen deprivation: WHIM16 patient-derived xenografts, C7-2-HI and C4-HI murine mammary adenocarcinomas, and long-term estrogen-deprived MCF-7 cells. As another means to reactivate ER, the anti-estrogen fulvestrant was withdrawn from fulvestrant-resistant MCF-7 cells. Transcriptional, growth, apoptosis, and molecular alterations in response to ER reactivation were measured. 17b-estradiol treatment and fulvestrant withdrawal induced transcriptional activation of ER, and cells adapted to estrogen deprivation or fulvestrant were hypersensitive to 17b-estradiol. ER transcriptional response was followed by an unfolded protein response and apoptosis. Such apoptosis was dependent upon the unfolded protein response, p53, and JNK signaling. Anti-cancer effects were most evident in models exhibiting genomic amplification of the gene encoding ER (ESR1), suggesting that engagement of ER at high levels is cytotoxic. These data indicate that long-term adaptation to estrogen deprivation or ER inhibition alters sensitivity to ER reactivation. In such adapted cells, 17b-estradiol treatment and anti-estrogen withdrawal hyperactivate ER, which drives an unfolded protein response activation and subsequent growth inhibition and apoptosis. 17b-estradiol treatment should be considered as an alternative therapy for anti-estrogen-resistant disease, particularly in patients with tumors harboring ESR1 amplification or overexpression. Furthermore, therapeutic strategies that enhance an unfolded protein response may enhance the therapeutic effects of ER reactivation.
2019-08-19 | GSE121379 | GEO
Project description:Retrospective series of primary breast cancer patients who received surgery between 1989 and 1992. Patients received adjuvant chemotherapy and/or adjuvant hormone therapy, or no adjuvant treatment. Tamoxifen was used as endocrine therapy for 5 years in ER+ BC patients. Patients who were <50 years of age, with lymph node positive tumors, or ER– and/or >3 cm in diameter, received adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) for six cycles, in a thrice weekly intravenous regimen. Patients >50 years of age with ER–, lymph node–positive tumors also received CMF.
2011-07-08 | GSE22219 | GEO
Project description:Retrospective series of primary breast cancer patients who received surgery between 1989 and 1992. Patients received adjuvant chemotherapy and/or adjuvant hormone therapy, or no adjuvant treatment. Tamoxifen was used as endocrine therapy for 5 years in ER+ BC patients. Patients who were <50 years of age, with lymph node positive tumors, or ER– and/or >3 cm in diameter, received adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) for six cycles, in a thrice weekly intravenous regimen. Patients >50 years of age with ER–, lymph node–positive tumors also received CMF.
2011-07-08 | GSE22216 | GEO