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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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE43146 | GEO | 2012/12/27

SECONDARY ACCESSION(S): PRJNA184722

REPOSITORIES: GEO

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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. 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.

2012-12-27 | E-GEOD-43146 | biostudies-arrayexpress

Lysine-specific demethylase 1 metastasis of androgen-independent PCa cells [RNA-seq]

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Lysine-specific demethylase 1 metastasis of androgen-independent PCa cells [ChIP-seq]

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Genistein treatment effects upin human prostate

Project description:Prior studies support the notion that the experimental chemopreventive agent, genistein, inhibits prostate cancer (PCa) cell movement in humans and that this in turn inhibits metastatic spread, thereby preventing PCa-specific death. As many effects have been ascribed to genistein, it has been considered a non-specific agent. However, its effects are concentration-dependent, and the vast majority of studies use concentrations greater than 3 logs above those associated with dietary consumption. Genistein is found in soy, and individuals consuming soy-based diets have blood concentrations of free genistein in the low nanomalar range. Using dosing guided by phase I pharmacokinetic studies in US men, prospective treatment of men on a phase II trial with genistein for one month prior to radical prostatectomy for localized PCa. Here we conducted an unbiased screening for effects of genistein in prostate as well as evaluate changes between normal and cancer cells.

2019-03-16 | GSE128339 | GEO

Homo sapiens

Project description:ERβ activation by genistein promotes metastatic progression in prostate cancer

| PRJNA184722 | ENA

Gene expression profiling of LNCaP cells following shRNA-mediated knockdown of TMEFF2 and growth in presence and absence of dihydrotestosterone

Project description:TMEFF2 is an androgen regulated transmembrane protein mainly restricted to brain and prostate, that functions as a tumor suppressor in prostate cancer (PCa). Studies using publically available prostate cancer (PCa) datasets, reveal changes in the expression of TMEFF2 with disease stage, supporting an important role of TMEFF2 in this disease. However, the role of TMEFF2 in the biology and pathogenesis of PCa is still unknown. Using a transgenic TMEFF2 mouse, we have demonstrated that TMEFF2 overexpression modulates prostate branching morphogenesis, and androgen regulated process, during prostate regeneration. We hypothesized that TMEFF2 may have a regulatory function within androgen signaling that could explain its role in PCa. To better understand its function in androgen signaling and PCa, we compared the transcriptome of LNCaP prostate cancer cells transduced with control shRNA and shRNA targeting TMEFF2 in the presence and absence of dihydrotestosterone (DHT). The results indicated that globally, there is a significant interaction between the effects of DHT and shTMEFF2. Of the 519 genes with significant gene expression changes after DHT treatment of Scramble control cells, 208 (40%) had significant differential expression when the shTMEFF2 +DHT group was compared to Scramble +DHT group, including numerous androgen activated and androgen repressed genes.

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Project description:Emerging evidence suggests that estrogen and prolactin (PRL) play a key role in prostate cancer development, yet their relationship and molecular actions in prostate is not well understood. To address this issue, we made the first direct comparison of estrogen and PRL actions in the Noble rat (NBL) prostate dysplasia model. Prostatic dysplasia in lateral prostate (DLP) has been induced by elevated circulating levels of estrogen and PRL in NBL with estrogen (E2)-filled implants, while physiological level of testosterone (T) was maintained with T-filled implants. The effect of estrogen and PRL was studied by using ICI and bromocriptine (Br) as their respective blockers, both can effectively inhibited dysplasia development under T+E2 induction. Transcript expression profile of the four treatment groups (Control, T+E2, T+E2+Br, and T+E2+ICI) has been characterized in this array.

2010-05-09 | E-GEOD-17819 | biostudies-arrayexpress

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.

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