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ERβ activation by genistein promotes metastatic progression in prostate cancer

ABSTRACT: Androgen signalling through the androgen receptor (AR) plays a critical role in prostate cancer (PCa) initiation and progression. Estrogen and the estrogen receptor, in synergy with androgen, are essential for cell growth of the normal and malignant prostate. However, the exact role that estrogen plays in prostate carcinogenesis, and the precise mechanisms involved, remain unclear. We have previously demonstrated the metastasis-promoting effect of an estrogen receptor Beta (ERβ) agonist (genistein) and the inhibitory action of an anti-estrogen (ICI 182, 780) in patient-derived PCa xenograft models mimicking localized and metastatic disease. In this study, we compared the gene expression profiles of treated and untreated PCa xenografts using microarrays to identify a unique set of genes that were both up-regulated by genistein treatment and down-regulated by the anti-estrogen, ICI 182,780. Five of the six genes identified from this comparison belonged to the metallothionein (MT) gene family. Knock-down of ERβ led to a reduction in MT gene expression, confirming its role in regulating these genes. Using qRT-PCR, the differences in expression levels were validated in the metastatic and non-metastatic LTL313 PCa xenograft tumour lines, both of which were originally derived from the same PCa patient. Together our data provides evidence for the role of ERβ signalling in PCa metastasis and implicates estrogen-stimulated MT gene expression in this process. Three samples each (total RNA extracted from three tumours of three different animals from each group) for control, genistein and ICI were used for the array.

ORGANISM(S): Homo sapiens

SUBMITTER: Hisae Nakamura

PROVIDER: E-GEOD-43146 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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ERβ activation by genistein promotes metastatic progression in prostate cancer

Project description:Androgen signalling through the androgen receptor (AR) plays a critical role in prostate cancer (PCa) initiation and progression. Estrogen and the estrogen receptor, in synergy with androgen, are essential for cell growth of the normal and malignant prostate. However, the exact role that estrogen plays in prostate carcinogenesis, and the precise mechanisms involved, remain unclear. We have previously demonstrated the metastasis-promoting effect of an estrogen receptor Beta (ERβ) agonist (genistein) and the inhibitory action of an anti-estrogen (ICI 182, 780) in patient-derived PCa xenograft models mimicking localized and metastatic disease. In this study, we compared the gene expression profiles of treated and untreated PCa xenografts using microarrays to identify a unique set of genes that were both up-regulated by genistein treatment and down-regulated by the anti-estrogen, ICI 182,780. Five of the six genes identified from this comparison belonged to the metallothionein (MT) gene family. Knock-down of ERβ led to a reduction in MT gene expression, confirming its role in regulating these genes. Using qRT-PCR, the differences in expression levels were validated in the metastatic and non-metastatic LTL313 PCa xenograft tumour lines, both of which were originally derived from the same PCa patient. Together our data provides evidence for the role of ERβ signalling in PCa metastasis and implicates estrogen-stimulated MT gene expression in this process.

2012-12-27 | GSE43146 | GEO

Transcription profiling of human breast cancer cells (MCF-7) coexpressing ERalpha and Erbeta, treated with phytoestrogens

Project description:We used microarrays to detail the global transcriptional response mediated by ERalpha or ERbeta to the phytoestrogen genistein in the MCF-7 human breast cancer cell model. Experiment Overall Design: MCF-7 human breast cancer cells expressing endogenouse Estrogen Receptor Alpha (ERalpha) were infected with adenovirus carrying either estrogen receptor beta (AdERb) or no insert (Ad) at multiplicity of infection (moi) of 20. Cells were then treated with either vehicle control (veh), 6nM 17beta-estradiol (E2), 6nM genistein (LG), 300nM genistein (HG), 300nM S-Equol (EQ), HG+3uM ICI182,780 (IG), EQ+3uM ICI 182,780(IE) for a additional periods of 4h or 24hr before RNA extraction and hybridization on Affymetrix microarrays. We sought to determine if genistein and S-Equol, phytoestrogens selective for the ERbeta can elicit transcriptional response distinctive from those mediated by the ERalpha.

2008-04-10 | E-GEOD-9936 | biostudies-arrayexpress

A quantitative proteomic based approach to study the genistein induced epigenetic reprogramming in MDA-MB231 cells

Project description:Epidemiological data indicate that consumption of soy-based food significantly reduces the cancer risk in human through interaction with estrogen receptors and the ‘phytoestrogen’ genistein present in the soy is responsible for this chemopreventive activity. The epigenome regulatory effect of genistein also reported but the key mechanism behind this effect remain elusive. In this current project, we reported the epigenome modulation effect of genistein using MDA-MB231 cells. Cells were treated with low-dose genistein for >1 month and the stable epigenetic alterations were analyzed by partial MNase digestion and TMT-based quantitative proteomics based chromatome mapping approach. We identified a total of 3177 chromatin-bound proteins with high confidence, including 882 proteins that displayed altered binding topology after cell conditioning with genistein. Prolonged phytochemical exposure permanently modified the binding topology of the key epigenetic regulators and preserved their binding topology in untreated progeny. Genistein induced altered epigenome modulation negatively regulates the expression of cell proliferation genes and suppress cell growth. In contrast, previously exposed cells displayed reduced expression of DNA repair genes and enhanced genotoxic stress upon genistein withdrawal.

2018-07-05 | PXD006178 | Pride

Quantitative Phosphoproteomics Reveals Genistein as a Modulator of Cell Cycle and DNA Damage Response Pathways

Project description:Around one sixth of breast cancer cases are classified as triple-negative breast cancer (TNBC), named after the absence of the expression of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2); however, patients with TNBC suffer from poor clinical outcome and shortage of targeted therapy. Genistein, an estrogenic soy isoflavone, shows anti-cancer effects in TNBC cells such as inducing G2/M cell cycle arrest and apoptosis. However, the underlying mechanism of its anti-cancer effects is poorly understood and its elucidation can help the development of novel therapeutic strategies for TNBC. In this study, by combining isobaric tag-based TMT labeling with titanium dioxide-based phosphopeptide enrichment, we quantitated 5,445 phosphorylation sites on 2,008 phosphoproteins in a TNBC cell line, MDA-MB-231, upon genistein treatment. Our analysis revealed 332 genistein-regulated phosphorylation sites on 226 proteins. Our data show that genistein can regulate several biological processes during the cell cycle, including DNA replication, cohesin complex cleavage, and kinetochore formation. In the meantime, genistein can also activate DNA damage response, including activation of ATR and BRCA1 complex. Overall, for the first time, our study present the evidence that genistein could inhibit TNBC cell growth by regulating the cell cycle and DNA damage response. Our findings help elucidate the mechanisms through which genistein exerts its anti-cancer effects in TNBC cells.

2016-01-26 | PXD002735 | Pride

Dietary Genistein Prevents Denervation-Induced Muscle Atrophy in Male Rodents via Effects on Estrogen Receptor-α.

Project description:Genistein is one of the flabonoids which is included in high concentration in soy and has a high estrogenic activity. Beneficial effects of estrogen or hormone replacement therapy (HRT) on muscle mass or muscle atrophy have been demonstrated. We investigated the preventive effects and underlying mechanisms of genistein intake on denervation-induced muscle atrophy. Genistein intake significantly suppressed the loss of soleus muscle weight and the denervation-induced up-regulations of FOXO1 protein. The results of a DNA microarray showed that the estrogen receptor (ER) target genes are changed by genistein intake. Genistein suppressed the soleus muscle atrophy, and it was attenuated under the ER antagonist treatment. The administration of an ERα agonist suppressed the denervation-induced muscle atrophy and up-regulation of Atrogin1 gene expression, but the ERβ agonist had no effect.

2016-01-23 | GSE77121 | GEO

Comparison of B. japonicum 110spc4 (wild type) induced versus uninduced

Project description:An initializing step in the rhizobia-legume symbiosis is the secretion of flavonoids by plants that leads to the expression of nodulation genes in rhizobia. Here we report the genome-wide transcriptional response of Bradyrhizobium japonicum to genistein, an isoflavone secreted by soybean. About 100 genes were induced in the wild type. This included all nod box-associated genes, the flagellar cluster and several genes that are likely to be involved in transport processes. To elucidate the role of known regulators, we analysed mutant strains. This revealed that the two-component response regulator NodW is essential for induction of almost all genistein-inducible genes, with the exception of 8 genes. The phenotype of the nodW mutant could be partially suppressed by overexpression of NwsB, which is also a two-component response regulator. These data indicate that genistein has a much broader function than mere induction of nod genes. Keywords: transcriptional analysis, genistein induction 3 biological replicates of wild type uninduced and wild type induced with genistein were compared.

2007-10-15 | E-GEOD-8571 | biostudies-arrayexpress

Comparison of B. japonicum mutant strain 613 induced versus wild type uninduced

Project description:An initializing step in the rhizobia-legume symbiosis is the secretion of flavonoids by plants that leads to the expression of nodulation genes in rhizobia. Here we report the genome-wide transcriptional response of Bradyrhizobium japonicum to genistein, an isoflavone secreted by soybean. About 100 genes were induced in the wild type. This included all nod box-associated genes, the flagellar cluster and several genes that are likely to be involved in transport processes. To elucidate the role of known regulators, we analysed mutant strains. This revealed that the two-component response regulator NodW is essential for induction of almost all genistein-inducible genes, with the exception of 8 genes. The phenotype of the nodW mutant could be partially suppressed by overexpression of NwsB, which is also a two-component response regulator. These data indicate that genistein has a much broader function than mere induction of nod genes. Keywords: transcriptional analysis, genistein induction 3 biological replicates of wild type (uninduced) and mutant strain 613 (nodW mutant; induced with genistein) were compared.

2007-10-15 | E-GEOD-8572 | biostudies-arrayexpress

Comparison of B. japonicum mutant strain M-NM-^T901 induced versus wild type uninduced

Project description:An initializing step in the rhizobia-legume symbiosis is the secretion of flavonoids by plants that leads to the expression of nodulation genes in rhizobia. Here we report the genome-wide transcriptional response of Bradyrhizobium japonicum to genistein, an isoflavone secreted by soybean. About 100 genes were induced in the wild type. This included all nod box-associated genes, the flagellar cluster and several genes that are likely to be involved in transport processes. To elucidate the role of known regulators, we analysed mutant strains. This revealed that the two-component response regulator NodW is essential for induction of almost all genistein-inducible genes, with the exception of 8 genes. The phenotype of the nodW mutant could be partially suppressed by overexpression of NwsB, which is also a two-component response regulator. These data indicate that genistein has a much broader function than mere induction of nod genes. Keywords: transcriptional analysis, genistein induction 3 biological replicates of wild type (uninduced) and mutant strain M-NM-^T901 (overexpressed nwsB; induced with genistein) were compared.

2007-10-14 | E-GEOD-8570 | biostudies-arrayexpress

Genistein Cooperates with the Histone Deacetylase Inhibitor Vorinostat to Induce Cell Death in Prostate Cancer Cells (expression data)

Project description:We have investigated the effects of genistein on several prostate cancer cell lines, including the ARCaP-E/ARCaP-M model of the epithelial-to-mesenchymal transition (EMT), to analyze effects on their epigenetic state. In addition, we investigated the effects of combined treatment of genistein with the histone deacetylase inhibitor vorinostat on survival in prostate cancer cells. Using whole-genome expression profiling and whole-genome methylation profiling, we have determined the genome-wide differences in genetic and epigenetic responses to genistein in prostate cancer cells before and after undergoing the EMT. Also, cells were treated with genistein, vorinostat, and a combination treatment, where cell death and cell proliferation was determined. ARCaP-E and ARCaP-M cells were analyzed for whole genome expression using the Illumina HumanHT-12 Expression BeadChip. Samples were treated with DMSO control, genistein, vorinostat, a combination of vorinostat and genistein, or 5-aza-deoxycytidine. Samples were prepared in triplicate on independent days.

2012-12-01 | E-GEOD-35242 | biostudies-arrayexpress

Genome-wide microarray analysis of normal human fibroblasts in response to kaemferol, daidzein, kaemferol/genistein, and daidzein/genistein

Project description:Establishment of a transcriptomic profile of human cells treated with kaemferol, daidzein, kaemferol/genistein, or daidzein/genistein with particular emphasis on signature of genes coding for enzymes involved in glycosaminoglycan synthesis stands for the present study. The hypothesis tested was that kaemferol, daidzein, kaemferol/genistein, and daidzein/genistein influence expression of some genes, among which are those coding for enzymes required for the synthesis of different GAGs being pathologically accumulated in mucopolysaccharidoses. Results provide important information concerning the extent of action of kaemferol, daidzein, kaemferol/genistein, and daidzein/genistein at the molecular level in terms of modulation of gene expression. Total RNA was obtained from human dermal fibroblasts (HDFa) subjected to 24 or 48 hours in vitro exposure to 30, 60 or 100 M-BM-5M kaemferol; 60 or 100 M-BM-5M daidzein; 30 M-BM-5M + 30 M-BM-5M kaemferol/genistein; 30 M-BM-5M + 30 M-BM-5M daidzein/genistein; or 0.05%DMSO. Three replicates each.

2013-01-24 | E-GEOD-43692 | biostudies-arrayexpress

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