Androgen Signaling in Prostate Cancer

Dai, Charles; Heemers, Hannelore V.; Sharifi, Nima

doi:10.1101/cshperspect.a030452

Cited by 316 publications

(286 citation statements)

References 199 publications

(181 reference statements)

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“…Among them, salivary duct carcinoma is the most frequent AR-expressing cancer, ranging from 64 to 98% of the cases. Excessive activation of AR signaling is strongly associated with the prognosis and malignancy of cancers in the salivary glands, prostate and breast (Dai et al, 2017;Giovannelli et al, 2018;Robinson et al, 2015). Interestingly, several studies indicate that expression of NRF2 and NRF1 is associated with prostate cancers via AR transactivation in humans and mice (Frohlich et al, 2008;Schultz et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Cholesterol metabolism plays a crucial role in the regulation of autophagy for cell differentiation of granular convoluted tubules in male mouse submandibular glands

et al. 2019

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It has been long appreciated that sex hormone receptors are expressed in various non-gonadal organs. However, it remains unclear how sex hormones regulate the morphogenesis of these nongonadal organs. To address this issue, we used a male mouse model of androgen-dependent salivary gland morphogenesis. Mice with excessive cholesterol synthesis in the salivary glands exhibited defects in the maturation of granular convoluted tubules (GCTs), which is regulated through sex hormone-dependent cascades. We found that excessive cholesterol synthesis resulted in autophagy failure specifically in the duct cells of salivary glands, followed by the accumulation of NRF2, a transcription factor known as one of the specific substrates for autophagy. The accumulated NRF2 suppressed the expression of Foxa1, which forms a transcriptional complex with the androgen receptor to regulate target genes. Taken together, our results indicate that cholesterol metabolism plays a crucial role in GCT differentiation through autophagy.

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Section: Discussionmentioning

confidence: 99%

Cholesterol metabolism plays a crucial role in the regulation of autophagy for cell differentiation of granular convoluted tubules in male mouse submandibular glands

et al. 2019

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“…Amplification of the AR gene locus or point mutations in the AR gene occurs in 60% of tumors that have been subjected to androgen ablation therapy (3). The appearance of ligand-independent AR splice variants or AR posttranslational modification may also contribute to continued AR activation following castration (4). Other common genetic alterations in AR-expressing CRPC include heterozygous deletions of PTEN and, to a lesser extent, p53 inactivation or loss of Rb1 expression (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Proteogenomic Characterization of Patient-Derived Xenografts Highlights the Role of REST in Neuroendocrine Differentiation of Castration-Resistant Prostate Cancer

Flores‐Morales

Bergmann

Lavallee

et al. 2019

Clinical Cancer Research

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Purpose: An increasing number of castration-resistant prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) features. NE prostate cancer (NEPC) has poor prognosis, and its development is poorly understood.Experimental Design: We applied mass spectrometrybased proteomics to a unique set of 17 prostate cancer patient-derived xenografts (PDX) to characterize the effects of castration in vivo, and the proteome differences between NEPC and prostate adenocarcinomas. Genome-wide profiling of REST-occupied regions in prostate cancer cells was correlated to the expression changes in vivo to investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation.Results: An average of 4,881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell-cycle regulation, and DNA repair were found upregulated and elevated in NEPC, while the reduced levels of proteins involved in mitochondrial functions suggested a prevalent glycolytic metabolism of NEPC tumors. Integration of the REST chromatin bound regions with expression changes indicated a direct role of REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell-cycle arrest in G 1 , which could be rescued by p53 knockdown. Finally, the expression of the REST-regulated gene secretagogin (SCGN) correlated with an increased risk of suffering disease relapse after radical prostatectomy.Conclusions: This study presents the first deep characterization of the proteome of NEPC and suggests that concomitant inhibition of REST and the p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer.

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“…Metastatic prostate cancer generally responds to androgen deprivation therapy (i.e., medical or surgical castration) but the tumor eventually progresses as castration-resistant prostate cancer (CRPC), which develops by way of tumor synthesis of testosterone and/or dihydrotestosterone (DHT) and other mechanisms that stimulate the androgen receptor (AR)(Attard et al, 2015; Dai, In press; Watson et al, 2015). Abiraterone and enzalutamide are 2 next-generation hormonal therapies that have a profound effect on metastatic disease, prolong survival and are FDA-approved for treatment of CRPC.…”

Section: Introductionmentioning

confidence: 99%

Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities

Alyamani

Berk

et al. 2017

Cell Chemical Biology

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SUMMARY Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist and AR degrader, and was under evaluation in a phase III clinical trial for castration-resistant prostate cancer (CRPC). The A/B steroid ring (Δ5, 3β-hydroxyl) structure of galeterone is identical to cholesterol, which makes endogenous steroids with the same structure (e.g., DHEA and pregnenolone) substrates for the enzyme 3β-hydroxysteroid dehydrogenase (3βHSD). We found that galeterone is metabolized by 3βHSD to Δ4-galeterone (D4G), which is further converted by steroid-5α-reductase (SRD5A) to 3-keto-5α-galeterone (5αG), 3α-OH-5α-galeterone, 3β-OH-5α-galeterone, and in vivo is also converted to the 3 corresponding 5β-reduced metabolites. D4G inhibits steroidogenesis, suppresses AR protein stability, AR target gene expression and xenograft growth comparably to galeterone, and further conversion by SRD5A leads to loss of several activities that inhibit the androgen axis that may compromise clinical efficacy. Together, these findings define a critical metabolic class effect of steroidal drugs with a Δ5, 3β-hydroxyl structure.

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Androgen Signaling in Prostate Cancer

Cited by 316 publications

References 199 publications

Cholesterol metabolism plays a crucial role in the regulation of autophagy for cell differentiation of granular convoluted tubules in male mouse submandibular glands

Cholesterol metabolism plays a crucial role in the regulation of autophagy for cell differentiation of granular convoluted tubules in male mouse submandibular glands

Proteogenomic Characterization of Patient-Derived Xenografts Highlights the Role of REST in Neuroendocrine Differentiation of Castration-Resistant Prostate Cancer

Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities

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