Androgen receptor signalling driving cancer stem cells (CSCs) state in triple-negative breast cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE184647 | GEO | 2023/12/03
REPOSITORIES: GEO
Similar Datasets
Project description:Therapeutic strategies that improve survival outcomes for advanced-stage breast cancers have proven a major clinical challenge. Here, we define an androgen receptor signalling network that governs the maintenance and de novo formation of cancer stem cells in triple-negative breast cancer. In response to chemotherapy, androgen receptor activation switches cells into a cancer stem cell state, while androgen receptor antagonism suppresses cancer stem cell formation and function. In vivo, we validate that the androgen receptor antagonist, seviteronel, significantly improves chemotherapy-mediated inhibition of primary and metastatic tumour growth.
2023-12-03 | GSE184455 | GEO
Project description:Triple-negative breast cancer (TNBC) is aggressive and difficult, and few targeted therapies are available to treat this patient population. The androgen receptor (AR) has emerged as a potential target in breast cancer. Newer generation AR inhibitors, such as Seviteronel (Sevi), are unique in their ability to inhibit AR both directly and by blocking upstream androgen synthesis. The purpose of this study was to investigate the pre-clinical activity of Sevi in TNBC and further explore the effectiveness of targeting both androgen biosynthesis and AR activity in combination with other downstream acting agents. AR overexpressing (AR+) TNBC cell lines, xenografts and androgen responsive patient-derived xenograft (PDX) models were using to show how effectively Sevi inhibits AR activity and cell/tumor proliferation. Single cell RNA-sequencing of the AR+ cell line MDA-MB-453 illustrated heterogeneity in AR levels and identified cell cycle pathway activation in ARHigh versus ARLow expressing cells. Combination treatment with the cell cycle CDK4/6 inhibitor abemaciclib and Sevi showed synergy in AR+ TNBC cells and increased effectiveness, compared to each drug alone, in an AR+ TNBC xenograft model. While cell cycle inhibitors have been approved for use in hormone-receptor positive breast cancer, our studies suggest that these drugs may be equally effective in AR+ TNBC cells, especially when combined with AR antagonists. Implications. These data suggest that targeting AR signaling at multiple points throughout the pathway may be an effective was to treat patients with AR+ TNBC.
2020-06-12 | GSE152318 | GEO
Project description:Triple-negative breast cancer (TNBC) is aggressive and difficult, and few targeted therapies are available to treat this patient population. The androgen receptor (AR) has emerged as a potential target in breast cancer. Newer generation AR inhibitors, such as Seviteronel (Sevi), are unique in their ability to inhibit AR both directly and by blocking upstream androgen synthesis. The purpose of this study was to investigate the pre-clinical activity of Sevi in TNBC and further explore the effectiveness of targeting both androgen biosynthesis and AR activity in combination with other downstream acting agents. AR overexpressing (AR+) TNBC cell lines, xenografts and androgen responsive patient-derived xenograft (PDX) models were using to show how effectively Sevi inhibits AR activity and cell/tumor proliferation. Single cell RNA-sequencing of the AR+ cell line MDA-MB-453 illustrated heterogeneity in AR levels and identified cell cycle pathway activation in ARHigh versus ARLow expressing cells. Combination treatment with the cell cycle CDK4/6 inhibitor abemaciclib and Sevi showed synergy in AR+ TNBC cells and increased effectiveness, compared to each drug alone, in an AR+ TNBC xenograft model. While cell cycle inhibitors have been approved for use in hormone-receptor positive breast cancer, our studies suggest that these drugs may be equally effective in AR+ TNBC cells, especially when combined with AR antagonists. Implications. These data suggest that targeting AR signaling at multiple points throughout the pathway may be an effective was to treat patients with AR+ TNBC.
2020-06-12 | GSE152315 | GEO
Project description:Triple-negative breast cancer (TNBC) is aggressive and difficult, and few targeted therapies are available to treat this patient population. The androgen receptor (AR) has emerged as a potential target in breast cancer. Newer generation AR inhibitors, such as Seviteronel (Sevi), are unique in their ability to inhibit AR both directly and by blocking upstream androgen synthesis. The purpose of this study was to investigate the pre-clinical activity of Sevi in TNBC and further explore the effectiveness of targeting both androgen biosynthesis and AR activity in combination with other downstream acting agents. AR overexpressing (AR+) TNBC cell lines, xenografts and androgen responsive patient-derived xenograft (PDX) models were using to show how effectively Sevi inhibits AR activity and cell/tumor proliferation. Single cell RNA-sequencing of the AR+ cell line MDA-MB-453 illustrated heterogeneity in AR levels and identified cell cycle pathway activation in ARHigh versus ARLow expressing cells. Combination treatment with the cell cycle CDK4/6 inhibitor abemaciclib and Sevi showed synergy in AR+ TNBC cells and increased effectiveness, compared to each drug alone, in an AR+ TNBC xenograft model. While cell cycle inhibitors have been approved for use in hormone-receptor positive breast cancer, our studies suggest that these drugs may be equally effective in AR+ TNBC cells, especially when combined with AR antagonists. Implications. These data suggest that targeting AR signaling at multiple points throughout the pathway may be an effective was to treat patients with AR+ TNBC.
2020-06-11 | GSE152246 | GEO
Project description:Changes in cellular lipid metabolism are a common feature in most solid tumors, which occur already in early stages of the tumor progression. However, it remains unclear if the tumor-specific lipid changes can be detected at the level of systemic lipid metabolism. The objective of this study was to perform comprehensive analysis of lipids in breast cancer patient serum samples. Lipidomic profiling using an established analytical platform was performed in two cohorts of breast cancer patients receiving neoadjuvant chemotherapy. The analyses were performed for 142 patients before and after neoadjuvant chemotherapy, and the results before chemotherapy were validated in an independent cohort of 194 patients. The analyses revealed that in general the tumor characteristics are not reflected in the serum samples. However, there was an association of specific triacylglycerols (TGs) in patients' response to chemotherapy. These TGs containing mainly oleic acid (C18:1) were found in lower levels in those patients showing pathologic complete response before receiving chemotherapy. Some of these TGs were also associated with estrogen receptor status and overall or disease-free survival of the patients. The results suggest that the altered serum levels of oleic acid in breast cancer patients are associated with their response to chemotherapy.
2014-06-17 | MTBLS92 | MetaboLights
Project description:The majority of breast cancer subtypes express androgen receptor (AR) in addition to estrogen receptor α (ERα). Depending on the breast cancer subtype androgen signaling has either stimulatory or inhibitory roles in breast cancer cell growth. We have mapped AR cistrome in ERα negative human molecular apocrine breast cancer MDA-MB453 cells and analyzed it in relation to the androgen-regulated transcriptome in the same cells. We have also examined the effect of silencing of the coregulator SUMO ligase PIAS1 on the androgen-regulated transcriptome and AR cistrome in MDA-MB453 cells. Our results show that the MDA-MB453 cells share with VCaP prostate cancer cells a core AR cistrome and target gene signature linked to cancer cell growth and that PIAS1 acts as an AR target gene-selective coregulator in MDA-MB453 cells.
2016-07-18 | GSE70162 | GEO
Project description:The majority of breast cancer subtypes express androgen receptor (AR) in addition to estrogen receptor a (ERa). Depending on the breast cancer subtype androgen signaling has either stimulatory or inhibitory roles in breast cancer cell growth. We have mapped AR cistrome in ERa negative human molecular apocrine breast cancer MDA-MB453 cells and analyzed it in relation to the androgen-regulated transcriptome in the same cells. We have also examined the effect of silencing of the coregulator SUMO ligase PIAS1 on the androgen-regulated transcriptome and AR cistrome in MDA-MB453 cells. Our results show that the MDA-MB453 cells share with VCaP prostate cancer cells a core AR cistrome and target gene signature linked to cancer cell growth and that PIAS1 acts as an AR target gene-selective coregulator in MDA-MB453 cells.
2016-07-18 | GSE70161 | GEO
Project description:The majority of breast cancer subtypes express androgen receptor (AR) in addition to estrogen receptor α (ERα). Depending on the breast cancer subtype androgen signaling has either stimulatory or inhibitory roles in breast cancer cell growth. We have mapped AR cistrome in ERα negative human molecular apocrine breast cancer MDA-MB453 cells and analyzed it in relation to the androgen-regulated transcriptome in the same cells. We have also examined the effect of silencing of the coregulator SUMO ligase PIAS1 on the androgen-regulated transcriptome and AR cistrome in MDA-MB453 cells. Our results show that the MDA-MB453 cells share with VCaP prostate cancer cells a core AR cistrome and target gene signature linked to cancer cell growth and that PIAS1 acts as an AR target gene-selective coregulator in MDA-MB453 cells. MDA-MB453 cells were transfected with control siRNA (siNON) or PIAS1 siRNA (siPIAS1) for 72 h and treated 16 h with 10 nM R1881 or vehicle (ethanol). Total RNA was isolated and biological triplicate samples were analyzed by microarray.
2016-07-18 | E-GEOD-70162 | biostudies-arrayexpress
Project description:Chemotherapy resistant prostate cancer is a major clinical problem. When the prostate cancer has become androgen deprivation resistant, one of the few treatment regimens left is chemotherapy. There is a strong connection between a cancer’s stem cell like characteristics and drug resistance. By performing RNA-seq we observed several factors associated with stem cells being strongly up-regulated by the estrogen receptor β variants, β2 and β5. In addition, most of these factors were also up-regulated by hypoxia. One mechanism of chemotherapy resistance was expression of the hypoxia-regulated, drug transporter genes, where especially ABCG2 and MDR1 were shown to be expressed in recurrent prostate cancer and to cause chemotherapy resistance by efficiently transporting drugs like docetaxel out of the cells. Another mechanism was expression of the hypoxia-regulated notch3 gene, which causes chemotherapy resistance in urothelial carcinoma, although the mechanism is unknown. It is well known that hypoxic signaling is involved in increasing chemotherapy resistance. Regulation of the hypoxic factors, HIF-1α and HIF-2α is very complex and extends far beyond hypoxia itself. We have recently shown that two of the estrogen receptor β variants, estrogen receptor β2 and β5, bind to and stabilize both HIF-1α and HIF-2α proteins leading to expression of HIF target genes. This study suggests that increased expression of the estrogen receptor β variants, β2 and β5, could be involved in development of a cancer’s stem cell characteristics and chemotherapy resistance, indicating that targeting these factors could prevent or reverse chemotherapy resistance and cancer stem cell expansion.
2018-08-14 | GSE118449 | GEO
Project description:Dynamics of Breast Cancer under Different Rates of Chemoradiotherapy.
Mkango SB1, Shaban N1, Mureithi E1, Ngoma T2.
Author information
1
Department of Mathematics, University of Dar es Salaam, P.O. Box 35062, Dar es Salaam, Tanzania.
2
Department of Clinical Oncology, Muhimbili University of Health and Allied Sciences, P.O. Box 65000, Dar es Salaam, Tanzania.
Abstract
A type of cancer which originates from the breast tissue is referred to as breast cancer. Globally, it is the most common cause of death in women. Treatments such as radiotherapy, chemotherapy, hormone therapy, immunotherapy, and gene therapy are the main strategies in the fight against breast cancer. The present study aims at investigating the effects of the combined radiotherapy and chemotherapy as a way to treat breast cancer, and different treatment approaches are incorporated into the model. Also, the model is fitted to data on patients with breast cancer in Tanzania. We determine new treatment strategies, and finally, we show that when sufficient amount of chemotherapy and radiotherapy with a low decay rate is used, the drug will be significantly more effective in combating the disease while health cells remain above the threshold.
Copyright © 2019 Sara B. Mkango et al.
2020-01-20 | MODEL1912120005 | BioModels